Millaisia keuhkomuutoksia eri sidekudossairauksien yhteydessä
18/04/15 Sidonnaisuuteni kaupalliseen yritykseen (ky) viimeisten 2 v aikana Millaisia keuhkomuutoksia eri sidekudossairauksien yhteydessä esiintyy Rii:a Kaarteenaho Keuhkolääkäripäivät 19.3.2015 Kuopio Ky 1 Ky 2 Saanut ky:lta apurahan Ei Ei Omistan ky:n osakkeita Ei Ei Saanut ky:lta palkkaa/palkkion (luentopalkkion) GSK Eli Lilly Finland Mundipharma ResMed Suunnitellut koulutustilaisuuden ja saanut ky:lta palkkion Ei Ei Osallistunut kongressiin ky:n osittain tai kokonaan maksamana BoehringerIngelheim Intermune Osallistunut ky:n hallintoelinten toimintaan Ei Ei Olen työsuhteessa ky:een Ei Ei Vastaanottanut muuta tukea ky:lta Ei Ei Systeeminen sidekudossairaus ja keuhkot Esityksen sisältö • Sidekudostauteihin lii:yvät keuhkomuutokset • Sidekudostauteihin lii:yvät intersDDaaliset keuhkomuutokset – Nimet, lyhenteet, yleisyys, ennuste • Oireet ja diagnosDikka • Kaikkiin sidekudossairauksiin voi lii:yä monenlaisia keuhkomuutoksia – Suuret ja pienet ilmaDet, intersDDum, ilmaDlat, verisuonet, pleura • Tietyt keuhkomuutokset assosioituvat De:yihin sidekudostauteihin • SamanaikaisesD voi olla myös useita muutoksia – Autoimmuunivasta-‐aineet • IIM-‐ILD ja anDsyntetaasi-‐syndrooma • UCTD-‐ILD • Tosielämän poDlaita SidekudostauDen tavallisimmat keuhkomanifestaaDot CTD UIP NSIP OP Ilma.et Pleura Verisuo-‐ DAH net SSc ± +++ ± _ _ +++ _ RA ++ + + ++ ++ + ± SjS _ + ± ++ + + _ MCTD + ++ + + + ++ _ PM/DM (IIM) ± ++ +++ _ _ + _ SLE _ + + + +++ + ++ Maher TM, Semin Respir Crit Care Med 2014 Sidonnaisuuden laatu IntersDDaalisten keuhkosairauksien ryhmi:elyä Kaarteenaho & Jar\, Duodecim 127:197-‐207, 2011 1 moking-related interith combined emphyl practice, respiratory is increasingly diagsmokers on the basis nd-glass opacities and veolar lavage (smokphocytosis). c pulmonary fibrosis ogeneous with some nged periods, others ion, and still others online supplement). A literature search was performed to identify new publications that pertained to these key questions, assisted by two librarians experienced in literature searches for pulmonary diseases. Literature retrieved from Medline searches between 2000 and 2011 was used to produce this statement. The committee was divided into subgroups assigned to specific sections of the document. These subgroups reviewed the relevant literature and produced the first draft of their respective sections. These sections were compiled by the committee chair and a complete first draft was edited by the writing subcommittee. This document was reviewed and edited by all committee members before final review by the writing subcommittee. The revised document was approved by all authors. d and recognized to and NSIP). SUMMARY OF MAJOR REVISIONS OF THE IIP CLASSIFICATION lt to classify, often njury. In the revision of the IIP classification, the main entities are preserved (Table 1). However, there are several important changes. First, cryptogenic fibrosing alveolitis is removed, leaving idiopathic pulmonary (IPF) as the sole clinical • Yleisiä fibrosis perustaudin IIP term for this diagnosis. Second, idiopathic nonspecific interstitial pneumonia (NSIP) is now ekstra-‐arDkulaarisia • UIP/IPF accepted as a distinct clinical entity with removal of the term “promanifestaaDoita • NSIP visional” (2).kThird, major IIPs are distinguished from rare IIPs and • Suuria uolleisuuden • DAD/AIP unclassifiable cases. Fourth, rare histologic patterns of acute fibriaiheu:ajia nous and organizing pneumonia (AFOP) and interstitial pneumo• OP/COP • with Luokitellaan nykyisin distribution are recognized. Fifth, the nias a bronchiolocentric • LIP majorsamoin IIPs arekuin grouped into chronic fibrosing (IPF and NSIP; Fig• DIP bronchiolitis–interstitial ures 1idiopaa\set and 2), smoking-related (respiratory • RB-‐ILD interstitial pneumonia lung intersDDaaliset disease [RB-ILD] and desquamative pneumoniat (IIP) [DIP]; Figure 3), and acute/subacute IIPs (cryptogenic organizing • Luoki:elematon pneumonia [COP] and acute interstitial pneumonia [AIP]; Figure 4 and Table 2). Sixth, a clinical disease behavior classification is proposed. Last, molecular and genetic features are reviewed. to provide a clinical ng IIP cases. This is psy is available and hy is not diagnostic. cognized as a specific less well-defined hiscentric inflammation ular markers holds approaches. These cting prognosis and rporation of genetic onize the approach e IIPs. the 2002 American ety (ATS/ERS) class (IIPs) (1). Focus is escribed clinical entiribing new histologic and-alone document ginal 2002 IIP classion (1) defined seven ed terminology and l “gold standard” of amic integrated apMDD). The 2002 IIP f all clinical publica2011. The new infored in this update. n by the ATS Docuommittee in collabne supplement). An sembled. The panel eases (19 pulmonolts in evidence-based eral meetings were ltidisciplinary panel t, which were vetted committee believed e APPENDIX 1 in the 18/04/15 Sidekudostauteihin lii:yvät intersDDaaliset keuhkosairaudet (ILD) IIP:n radiologis-‐histologiset ja kliiniset nimet Histologia, radiologia Kliininen nimi • UIP (usual intersDDal pneumonia) • NSIP (nonspecific intersDDal pneumonia) • OP (organizing pneumonia) • IPF (idiopathic pulmonary fibrosis) • NSIP (nonspecific intersDDal pneumonia) • COP (cryptogenic organizing pneumonia) • AIP (acute intersDDal pneumonia) • DAD (diffuse alveolar damage) GENERAL PROGRESS IN IIPS SINCE 2002 Multidisciplinary Approach The process of achieving a multidisciplinary diagnosis in a patient with IIP is dynamic, requiring close communication between clinician, radiologist, and when appropriate, pathologist (1). Clinical data (presentation, exposures, smoking status, associated SidekudostauDen ja ILD-‐tauDen nimet IIP:n uusi luoki:elu (ATS/ERS 2013) TABLE 1. REVISED AMERICAN THORACIC SOCIETY/EUROPEAN RESPIRATORY SOCIETY CLASSIFICATION OF IDIOPATHIC INTERSTITIAL PNEUMONIAS: MULTIDISCIPLINARY DIAGNOSES Major idiopathic interstitial pneumonias Idiopathic pulmonary fibrosis Idiopathic nonspecific interstitial pneumonia Respiratory bronchiolitis–interstitial lung disease Desquamative interstitial pneumonia Cryptogenic organizing pneumonia Acute interstitial pneumonia Rare idiopathic interstitial pneumonias Idiopathic lymphoid interstitial pneumonia Idiopathic pleuroparenchymal fibroelastosis Unclassifiable idiopathic interstitial pneumonias* CTD ConnecDve Dssue disease CVD Collagen vascular disease RA Rheumatoid arthriDs MCTD Mixed connecDve Dssue disease SLE Systemic lupus erythematosus IIP vs CTD-‐ILD UIP NSIP OP DAD LIP RB-‐ILD/DIP Luoki:elematon IdiopaaBnen inters..aalinen pneumonia IPF NSIP COP AIP LIP RB-‐ILD/DIP Luoki:elematon RA-‐ILD RA-‐UIP RA-‐NSIP SSc Scleroderma * Causes of unclassifiable idiopathic interstitial pneumonia include (1) inadeTravis W et al, AJRCCM 2013 quate clinical, radiologic, or pathologic data and (2) major discordance between clinical, radiologic, and pathologic findings that may occur in the following situations: (a) previous therapy resulting in substantial alteration of radiologic or histologic findings (e.g., biopsy of desquamative interstitial pneumonia after steroid therapy, which shows only residual nonspecific interstitial pneumonia [153]); (b) new entity, or unusual variant of recognized entity, not adequately characterized by the current American Thoracic Society/European Respiratory Society classification (e.g., variant of organizing pneumonia with supervening fibrosis) (79); and (c) multiple high-resolution computed tomography and/or pathologic patterns that may be encountered in patients with idiopathic interstitial pneumonia. Histologinen ja/ tai radiologinen muutos CTD-‐ILD ConnecDve Dssue associated intersDDal lung disease Sidekudostau.in liiDyvä inters..aalinen muutos RA-‐UIP SSc-‐NSIP RA-‐OP SLE-‐DAD SjS-‐LIP (CTD-‐DIP) CTD-‐ILD REVIEWS PM/DM (IIM) Poly/dermato-‐ myosiDs (Idiopathic inflammatory myopathy) SSc-‐ILD SSc-‐NSIP MCTD-‐ILD MCTD-‐UIP SjS Sjögren syndrome Eri CTD-‐ILD-‐tyyppien yleisyys Table 1 | The relative prevalence of histological patterns in IIP in CTDs Lung pattern IIP Rheumatoid arthritis Systemic sclerosis SLE Polymyositis– dermatomyositis Sjögren syndrome Usual interstitial pneumonia +++ ++ + + + ± Nonspecific interstitial pneumonia ++ ++ +++ ++ ++ ++ Desquamative interstitial pneumonia and/or RB-ILD + ± ± ± ± ± Organizing pneumonia ++ + ± ± ++ ± Lymphocytic interstitial pneumonia ± ± ± ± ± ++ Pleuroparenchymal fibroelastosis ± ? ? ? ? ? Diffuse alveolar damage + + ± + + ± Abbreviations: ?, prevalence unknown; ±, rare; +, infrequent; ++, frequent, but not clearly in the majority of cases; +++, common, clearly in the majority of cases; CTD, connective tissue disease; IIP, idiopathic interstitial pneumonia; RB-ILD, respiratory bronchiolitis-associated interstitial lung disease; SLE, systemic lupus erythematosus. likewise, primary vasculitis or sarcoidosis commonly disease is more benign than in IPF, possibly linked to a cause parenchymal lung disease, but further discussion low profusion of fibroblastic foci at biopsy.48 A subset of these matters is beyond the Wells scope of&this Review. Nat Rev ofRpatients with2RA-associated UIP with a poor IPF Denton, heumatol 014 like outcome might be captured by high-resolution CT Classification of CTD-ILD (HRCT) appearances that are strongly indicative of UIP, Lung complications in CTDs with predominantly basal subpleural honeycomb change. The only currently used classification of CTD-ILD is In one study, patients with RA-associated ILD with this the histological classification of idiopathic interstitial feature on HRCT scan (n = 20; <25% of the cohort) had 39 pneumonia (IIP). All histological patterns seen in IIP the same poor outcome as patients with IPF (n = 51), are also reported to occur in CTD-ILD,40 apart from the despite less severe pulmonary function impairment at newly described pattern of pleuroparenchymal elastosis presentation.33 However, the remaining patients in this (which has yet to be completely clinically characterized). study, undoubtedly including a large proportion with However, the relative prevalence and prognostic imporunderlying UIP but no honeycomb appearance on HRCT, tance of histological patterns differs greatly between had a much better outcome. idiopathic disease and CTD-ILD (Table 1). In idiopathic Indirect evidence is available that UIP subsets exist disease, UIP, corresponding to IPF, is the most prevalent in RA (and possibly in other CTDs) with differences in pattern.41 IPF has a worse prognosis than other interoutcome. In a study examining biopsy samples, patients stitial lung disorders, including fibrotic NSIP, the other with RA-associated UIP (n = 19) had an overall survival predominantly fibrotic idiopathic disease.41 By contrast, that was intermediate between CTD-associated NSIP in CTD-ILD, NSIP is the most prevalent histological (n = 57) and IPF (n = 203).49 Although difficult to interpattern in ILD associated with SSc, 42 polymyositis– pret due to the small size of the RA-associated UIP subdermatomyositis43 and primary Sjögren syndrome,44 and group, survival in this group was clearly bimodal with is probably more prevalent than UIP in SLE, based on most deaths occurring within 12 months and survival our anecdotal clinical experience. Furthermore, in these similar to CTD-associated NSIP after the first year. When disorders, whether the histological distinction between compared with IPF, patients with CTD-associated UIP UIP and NSIP has prognostic importance is unclear. In had lower scores for fibroblastic foci and higher scores SSc-ILD, the most-studied disorder, a histological pattern for germinal centres and bronchocentric inflammation, of UIP was not associated with a worse outcome in the with these differences having prognostic significance.47 42 largest histological series of 78 patients, although this However, the range of scores was wide with substantial conclusion has been questioned in one small series, in overlap with IPF histological scores, suggesting that which UIP was associated with a very poor outcome.45 inflammation might be pathogenic in some, but not all, 2 18/04/15 REVIEWS Kuinka yleinen CTD-‐ILD on? Muiden keuhkomuutosten yleisyys Table 2 | The relative prevalence of pulmonary comorbidities, other than interstitial lung disease arising from CTD Lung complication Rheumatoid arthritis Systemic sclerosis SLE Polymyositis– dermatomyositis Sjögren syndrome Pulmonary hypertension disproportionate to ILD ± ++ ++ ± ± Bronchiectasis ++ ± + ± + Obliterative bronchiolitis + ± + ± + Diffuse alveolar haemorrhage ± ? + ± ? Pleural disease ++ ± ++ ± ± Respiratory muscle impairment ? ? ± + ? Abbreviations: ?, prevalence unknown; ±, rare; +, infrequent; ++, frequent, but not clearly in the majority of cases; +++, common, clearly in the majority of cases; CTD, connective tissue disease; ILD, interstitial lung disease; SLE, systemic lupus erythematosus. by HRCT67 and yet in large historical series, chest radioCTD-ILD, a pulmonary function profile of preservation graphic evidence of pulmonary fibrosis was present in of lung volumes and a severe reduction in DLCO can also only 2% of patients.68,69 In a series of >200 patients with represent the coexistence of ILD and smoking-related 72,73 SSc-ILD, the extent of interstitial Thus, a clear understanding of this Wells abnormalities & Denton, Nwas at Rev emphysema. Rheumatol 2014 minor or very mild (involving <10% of the lung) in >40% frequent pulmonary function profile in the individual of cases.70 patient with CTD-ILD requires the integration of HRCT Thus, although HRCT is sensitive, it might be too senand echocardiographic data. The principle of multisitive to serve as a useful screening tool for CTD-ILD in disciplinary evaluation applies equally to the delineation unselected patients with CTD. It follows logically that of symptom severity and pulmonary function impairHRCT should be used by protocol to confirm or exclude ment when the wide range of other pulmonary comorbidCTD-ILD only in higher risk groups (for example, ities in CTD-ILD is considered. In Table 2, the spectrum patients with SSc who are positive for anti-topoisomerase of chronic pulmonary comorbidities is shown with a or anti-RNA polymerase III antibodies) or when there is semiquantitative statement of relative prevalence in indireason to suspect the presence of CTD-ILD, according vidual CTDs. So-called multicompartment lung disease to symptoms, clinical examination, chest radiography or with variable airway, interstitial, pleural and pulmonary pulmonary function abnormalities. Optimal screening vascular components is a frequent clinical problem in protocols for CTD-ILD are currently being developed by CTD-ILD. In Box 1, the frequently encountered clinical a group of international experts. scenarios of multicompartment disease are shown with characteristic pulmonary function profiles. Evaluation of disease severity Given the sensitivity of HRCT, the identification of ILD Monitoring of ILD should be followed by a multidisciplinary evaluation The accurate monitoring of CTD-ILD is centred on serial of disease severity, with the integration of symptoms, pulmonary function testing. The FVC is highly reprothe severity of pulmonary function impairment and the ducible and in the absence of major extrapulmonary morphological extent of disease on HRCT. Amongst restriction due to pleural disease or muscle weakness, these measures, pulmonary function tests provide the changes in FVC are specific to ILD. Forced spirometric most precise measurement of disease severity. However, manoeuvres are occasionally contraindicated or difficult pulmonary function variables should not be interpreted to interpret due to glaucoma or clinically significant chest in isolation due to the confounding effect of the normal wall discomfort; for this reason, plethysmography is comrange, which is particularly misleading when there is mild monly performed at presentation (to provide an alternapulmonary function impairment. A reduction in FVC tive means of monitoring disease progression). Measures to 70% at presentation, for example, can be indicative of gas transfer are less reproducible than lung volumes equally of a relatively minor decrease of 10% or a major and are confounded by changes in pulmonary vascular reduction of 50% from premorbid values of 80% and limitation. On the basis of reproducibility data, serial 120%, respectively. In isolated ILD, typically, a restrictive pulmonary function trends are compatible with disease ventilatory defect exists, with reduced FVC and total lung progression only when a decline in FVC exceeds 10% capacity, an increased forced expiratory volume 1 to FVC of the baseline value or a decline in DL CO exceeds ratio of >0.8, and reduced carbon monoxide diffusing 15% of the baseline value (reflecting the greater varicapacity (DLCO) and lung compliance. ability of DLCO estimation). Even when these thresholds are exceeded, clinicians should consider alternative The problem of pulmonary comorbidities explanations for changes in pulmonary function tests, Reductions in DLCO that are disproportionate to lung including infection, pulmonary embolism, pulmonary volumes might result from coexistent pulmonary vashypertension and cardiac disease. As with the evalucular limitation: an elevation in the FVC:DLCO ratio ation of severity at presentation, combined clinical was found to be predictive of underlying pulmonary experience indicates that the evaluation of change is hypertension in the SSc DETECT study.71 However, in a multidisciplinary exercise requiring the integration Ovatko CTD-‐ILD:t yleistyneet? • Perussairauden ennuste parantunut – Enemmän poDlaita, joilla myös keuhkomanifestaaDo – Onko todellistakin lisääntymistä? • Yksi:äisinä harvinaisia – Vain suurissa keskuksissa runsaasD poDlaita • Tutkimuksiin vaikeaa saada rii:ävää poDlasmäärää ilman monikeskustutkimuksia • Viime vuosiin saakka luoki:elu puu:unut ja nimikkeistöä käyte:y kirjavasD 734 | DECEMBER 2014 | VOLUME 10 www.nature.com/nrrheum © 2014 Macmillan Publishers Limited. All rights reserved Moua et al. Respiratory Research 2014, 15:154 http://respiratory-research.com/content/15/1/154 RESEARCH Open Access Predictors of diagnosis and survival in idiopathic pulmonary fibrosis and connective tissue disease-related usual interstitial pneumonia Teng Moua*, Ana C Zamora Martinez, Misbah Baqir, Robert Vassallo, Andrew H Limper and Jay H Ryu Abstract -‐ Biopsoidut UIP-‐fibroosit analysoiDin uudelleen -‐ 625 tapausta, joista 89 CTD-‐UIP -‐ Mayo Clinicissa tutkitut poDlaat 1995-‐2010 Results: Six hundred and twenty five patients were included in the study of which 89 had diagnosed CTD-UIP representing 7 disease entities. Survival was better among those with CTD-UIP except in UIP associated with rheumatoid -‐ Kliinis-‐radiologis-‐histologinen re-‐analyysi, elinaika arthritis, which had similar presenting features and survival to IPF. Predictors of underlying CTD included female gender, Background: Although usual interstitial pneumonia (UIP) appears to portend better survival when associated with connective tissue disease (CTD-UIP), little is known about the presenting clinical, radiologic, and pathologic features that differentiate pathologically confirmed UIP with CTD from idiopathic pulmonary fibrosis (IPF). In patients with atypical radiologic and clinical features, what specific findings predict underlying IPF vs. CTD-UIP diagnosis and their respective long term survival? Methods: A large retrospective cohort analysis was done of consecutive patients seen from 1995 through 2010 with biopsy confirmed UIP completed or reviewed at our institution. CTD-UIP was defined by independent rheumatology consultation with exclusion of all other secondary causes of lung fibrosis. Primary clinical data was collected and compared for IPF and CTD-UIP along with logistic regression performed for predictors of disease likelihood and Cox proportional hazards analysis for predictors of survival. younger age, positive autoimmune serology, and inconsistent presenting radiologic findings. Only age and forced vital capacity corrected for a priori covariates were predictive of survival in CTD-UIP. Conclusions: UIP pathology occurs frequently Moya among et al, Rpatients espir with Res atypically 2014 presenting clinical and radiologic features, and may represent IPF or CTD-UIP with improved prognosis if underlying CTD is diagnosed. Presenting radiologic and pathologic features alone are not predictive of underlying secondary cause or survival between the two groups. Keywords: Idiopathic pulmonary fibrosis, Usual interstitial pneumonia, Connective-tissue disease interstitial lung disease Introduction Usual interstitial pneumonia (UIP) is characterized by temporally heterogenous parenchymal fibrosis with architectural distortion, interstitial thickening, fibroblast foci, and honeycombing [1]. Although a defining pathologic finding in idiopathic pulmonary fibrosis (IPF), it has been found in other chronic fibrotic lung disease such as the connective tissue-disease associated interstitial lung disease (CTD-ILD) [2,3], chronic hypersensitivity pneumonitis (HP) [4], sarcoidosis [5], and advanced asbestosis [6]. * Correspondence: [email protected] Division of Pulmonary and Critical Care Medicine, Mayo Clinic, 200 First St. SW, Rochester, MN 55901, USA Current classification of the idiopathic interstitial pneumonias (IIP) allows not only pathological distinction of fibrotic disease, but implied characteristic clinical and prognostic significance [7]. For example, it is well known that UIP has worse prognosis than non-specific interstitial pneumonia (NSIP), the two most commonly presenting pathologies [8,9]. Both again may be idiopathic or associated with known etiologies, which has clinical significance in terms of survival and response to therapy [10]. Prior studies have suggested secondary UIP such as that seen in certain connective-tissue diseases (CTD-UIP) may have better prognosis and survival than IPF [2,10]. Other studies have been conflicting regarding better survival in difficult to diagnose CTD or all CTD-ILD [11,12]. Specific © 2014 Moua et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. • Radiologisissa tutkimuksissa prevalenssi 33-‐57% – RA-‐ILD 10%, SSc-‐ILD 20-‐25%, PM/DM 20-‐78% • Muitakin syitä ILD:lle voi olla – Lääkkeet – InfekDot – Muut ILD:n aiheu:ajat (allerginen alveolii\) – MaligniteeDt Onko ILD:n tyypillä mitään merkitystä poDlaan hoidon kannalta? • Osassa ei selkeää ennusteellista eroa olipa kyseessä NSIP tai UIP (esim. SSc) • RA-‐UIP:n ennuste huonompi kuin RA-‐NSIP:n Moua et al. Respiratory Research 2014, 15:154 http://respiratory-research.com/content/15/1/154 Page 6 of 9 Table 6 Subgroup analysis of clinical predictors of death in IPF Univariable HR (95% CI) P value Multivariable, HR (95% CI) P value Age at biopsy 1.03 (1.02-1.04) <0.0001 1.03 (1.01-1.04) 0.0002 Gender (male risk) 1.48 (1.15-1.93) 0.003 1.52 (1.15-2.02) 0.003 Smoking Hx 1.13 (0.88-1.46) 0.34 1.04 (0.77-1.37) 0.79 Duration of symptoms prior to biopsy 0.99 (0.99-1.00) 0.51 0.99 (0.99-1.00) Autoimmune serology 0.89 (0.65-1.19) 0.43 0.95 (0.69-1.27) 0.72 GERD 1.05 (0.82-1.35) 0.66 1.02 (0.80-1.31) 0.87 – Sekamuotojen esiintyminen vaikeu:aa usein diagnosDikkaa • OP paranee yleensä steroidilla, joten tärkeää ero:aa muista 0.40 FEV1, % pred 0.98 (0.98-0.99) 0.0004 0.99 (0.97-1.02) 0.53 FVC, % pred 0.98 (0.98-0.99) 0.0001 0.99 (0.98-0.99) 0.03 DLCO, % pred 0.99 (0.98-0.99) 0.0001 0.99 (0.98-0.99) 0.02 TLC, % et pred Moua al. Respiratory Research 2014, 15:154 0.98 (0.98-0.99) http://respiratory-research.com/content/15/1/154 0.0012 1.00 (0.99-1.02) Page0.65 7 of 9 Probable UIP 0.76 (0.56-1.04) 0.09 0.78 (0.57-1.08) 0.13 0.91 (0.65-1.27) 0.56 0.96 (0.69-1.35) 0.82 Initial HRCT pattern Probable NSIP or inconsistent with UIP 0.98 (0.67-1.35) 0.82 with CTD-ILD have 0.96 better prognosis than IPF, confirmatory biopsy appears unnecessary to justify treatment as response to therapy appears better among all pathologic subclasses. Even so, most patients undergoing biopsy do so as a result of clinical equipoise in defining early or Our main findings support better survival in patients atypical radiologic findings increased the risk of underatypical lung fibrosis radiologically with possible or inwith CTD-UIP compared to IPF, despite the presence of lying CTD diagnosis. Finally, despite CTD-UIP overall consistent IPF features and no clearly defined CTD or similar initial radiologic and PFT findings. Frequency of having better survival, RA-UIP had similar survival to IPF secondary cause. In our cohort, presenting radiologic positive autoimmune serologies was higher in CTD than with worse survival compared to other CTD-UIP in our and PFT findings were no different in those with susIPF, though still occurred in 29% of tested IPF patients. cohort. pected IPF and eventual CTD. Prior studies support the UIP represents a commonly found interstitial pneumoClinical predictors for survival in CTD-UIP were age relatively high frequency of positive autoimmune seroland FVC, compared to IPF which included additionally nia pattern whose defining features belie a heterogenously ogies in IPF further confounding diagnostic evaluation gender and DLCO. Atypical or additional pathologic progressive fibrotic process characterized by fibroblast in early disease [27,28]. Our study confirms that even findings such as organizing pneumonia, lymphoid aggre- foci and honeycombing. Characteristic pathologic findings among patients with UIP, female gender, younger age, Figureor 3 Survival in RA-UIP vs. all otherwere CTD-UIP; (P = frequently 0.0163 may be diagnosed variably among evaluating pathologists, gates, chronic inflammation more atypical CT findings, and positive autoimmune serology Log Rank). seen in CTD-UIP, but did not predict survival ((HR 0.83 though little is known about the prognostic features of were still predictive of subsequent CTD. On the other findings such as organizing pneumonia or lymph(0.59-1.14), P =0.27)in either cohort. In patientsPage with4 of atypical Moua et al. Respiratory Research 2014, 15:154 9hand UIP pathology with inconsistent UIP CT pattern pathologically confirmed UIP, younger age, female gen- oid hyperplasia in the setting of histopathologic UIP pathttp://respiratory-research.com/content/15/1/154 have suggested increased lymphoid aggregates [22] or occurs relatively frequently in IPF with similar survival der, presence of positive autoimmune serology, and tern other than their association with CTD. Prior studies hyperplasia [23] associated with underlying CTD, along to radiologically consistent disease. A recent study prowith decreased number of fibroblast foci [23,24]. The spe- poses perhaps increased frequency of acute exacerbation cific features of pathologic findings in UIP have also been in IPF compared to CTD-ILD as a reason for this differpredictive of survival in IPF, in particular the frequency of ence in survival, as deterioration of PFT findings over Table 2 Specific connective-tissue disease distributions Given the current UIP cohort was predominantly fibroblast foci [25]. The study by Park et al. compared time appeared similar between the two groups [29]. representative of IPFamong patients, CTD subtype (N = 89) N (%) pathologic features differingsubgroup ILD groupsanalysis and noted was In our pathologically defined cohort, UIP associated performed onsurvival CTD-UIP for clinicalwith RA appears to have similar clinical presentation improved amongand thoseIPF withseparately CTD-UIP compared RA 24 (27) to IPF of [2].survival Others have found no difference survival predictors (Tables 5 and 6). Whileinage, gender,and survival to IPF. In particular, RA patients were older SLE 2 (2) those with IPF and CTD-ILD [12] or withpre-with more male predominance compared to other CTDFVC,among and DLCO adjusted forgeneral a priori covariates were Scleroderma (systemic sclerosis) 13 (15) autoimmune dominant lung fibrosis [26] not fitting dictive of survival in IPF patients, only age and FVC CTD adjustedILD, and did worse despite similar presenting PFT and criteria. Little is known about the pathologic mechanisms CT patterns among all CTD patients. A recent study MCTD 2 (2) were that predictive in CTD-UIP. Initial univariable analysis suglead to a common final pathway of UIP pattern yet dif- suggested better survival in comparison to case-matched DM/PM 13 (15) gestedferent smoking andand FVC were An predictive rates ofhistory, disease FEV1, progression survival. under- inIPF controls who received treatment [30]. While an CTD standing but wereofno after correction for age and gender.NSIP CT pattern and histology are most common in Sjogren’s syndrome 5 (5) thelonger perhaps presumptive inflammatory-based mechanisms that lead being to UIP predictive in CTD-ILDof compared to the CTD-ILD, recent work suggests UIP CT features may Despite female gender CTD diagnosis, Undifferentiated CTD 30 (34) relatively unknown mechanisms in IPF may be helpful in occur more frequently than previously noted [31] and is gender was not predictive of survivalPage among et al. Respiratory Research 2014, 15:154 7 of 9 CTD patients CTDMoua = connective tissue disease, DM/PM = dermatomyositis/polymyositis, MCTD = with underlying pathology [20]. future IPF treatment approaches. http://respiratory-research.com/content/15/1/154 Figure consistent 2 Survival in IPF stratified by 5 yearUIP periods (1995–2010); mixed connective tissue disease, RA = rheumatoid arthritis, SLE = systemic whiledeciphering in IPF male gender portended worse survival in bothhighly radiologic features of advanced disease appear preOur study highlights several insights in comparing bi- Such (P = 0.03 Log Rank). Figure 1 Survival in IPF vs. CTD-UIP; (P = 0.0005 Log-rank). lupus erythematosus. univariable and multivariable opsy confirmed UIP in IPFanalysis. and CTD. As most patients dictive of survival similar to IPF, though in our cohort, Figure 1 compares transplant-free survival from biopsy tosimilar presenting radiologic patterns were seen between date of have deathbetter fromprognosis any cause mortality) betweenRA-UIP patients and other CTD-UIP (predominantly with CTD-ILD than(all-cause IPF, confirmatory biopsy appears unnecessary to justify treatment as was notablyatypical or probable UIP CT findings). As UIP pathology organizing pneumonia were predominant atypical IPF and CTD-UIP. Survival among CTD-UIP response to therapy appears among all pathologic pathologic findings seen in IPF. The majority of CTD better (median 79.4 better vs. 47.7 months, Log rank P = 0.0005). appears to bode worse survival, confirmatory biopsy in this subset of CTD-ILD particularly with atypical CT subclasses. Even so, most patients undergoing biopsy do diagnoses associated with UIP were UCTD (34%) and Figure 2 depicts survival in biopsy confirmed IPF pa-may not be unreasonable. Underlying mechanisms as to so as a result of clinical equipoise in defining early or RA (27%). tients stratified by 5 year intervals (a) 1995–1999, b)why RA-UIP may do poorly is currently unknown and atypical lung fibrosis radiologically with possible or inAmong patients with pathologically confirmed UIP, 2000–2004, c) and 2005–2010). appeared greatest inthe subject of ongoing study. consistent IPF features no clearly Survival defined CTD or younger age, female gender, positive autoimmune serpatients from presenting 2005–2010radiologic (median 58.3 (42.3- Survival in IPF is known to be variable and may be afsecondary cause. biopsied In our cohort, and PFT findings were and no different thosebiopsied with sus-between 2000–fected by multiple factors including disease severity at ology, and non-UIP consistent radiologic patterns un71.5) months) least in inthose the time of presentation and access to tertiary or expert pected 2004 IPF and eventual43.7 CTD. Prior studies support adjusted by logistic regression were predictive of CTD (median (34.2-48.9); (Log rank the P = 0.03)). care with earlier assessment [32]. Whether earlier diagrelatively As high CTD-UIP frequency ofrepresents positive autoimmune seroldiagnosis (Table 3). After adjusting for a priori covariates a heterogenous group ofnosis affects outcome remains tentative, as most patients ogies in IPF further confounding diagnostic evaluation (age, gender, smoking history, percent predicted FVC and underlying diseases, and there have been recent reports with consistent UIP pattern on CT likely represent more in early disease [27,28]. Our study confirms that even DLCO), age, positive autoimmune serology, and inconsistadvanced disease with worse survival. We note survival of rheumatoid related lung fibrosis representing more agamong patients with UIP, female gender, younger age, Figure 3 Survival in RA-UIP vs. all other CTD-UIP; (P = 0.0163 by 5 year intervals in our cohort suggest recently biopent Log CTRank). findings remained predictive of underlying CTD.atypicalgressive disease [20,21], subgroup analysis CT findings, positive autoimmune serology Figure 4 and Survival in RA-UIP vs. IPF; (P =0.76 Log Rank). of survival were still predictive of subsequent CTD. On the other Table 4 represents univariable and multivariable adamong RA-UIP vs all other CTD-UIP and IPF was per-sied patients had better survival than those biopsied a hand UIP pathology with inconsistent UIP3CT justed predictors of survival among all UIP patients. Iniformed and depicted in Figures andpattern 4. RA-UIP appears occurs to relatively frequently in IPF with similar survival suggested increased [22] or (HR tialhave unadjusted analysis lymphoid suggestedaggregates both smoking have worse survival compared to the other CTDs (mehyperplasia [23] associated with underlying CTD, along to radiologically consistent disease. A recent study pro1.32 [1.04-1.69], P =0.023) and positive autoimmune ser- dian 38 vs. 103.9 months, Log rank P =0.0163) with simiwith decreased number of fibroblast foci [23,24]. The spe- poses perhaps increased frequency of acute exacerbation ology of findings survivalin (HR 0.72,also[0.55-0.93], lar survival to IPF (Log rank Pfor=0.76). RA-UIP patients to CTD-ILD as a reason this differcific were featurespredictive of pathologic UIP have been in IPF compared P =predictive 0.02), though were noin longer after olderas and predominantly ence inwere survival, deterioration of PFT male, findingsthough over with similar of survival in IPF, particularpredictive the frequency of corbetween two groups [29]. fibroblast The FVC, study by et al. compared time appeared rection for foci age,[25]. gender, andPark DLCO. baselinesimilar CT and PFTthefindings compared to other CTDIn our pathologically defined cohort, UIP associated pathologic features among differing ILD groups and noted improved survival among those with CTD-UIP compared with RA appears to have similar clinical presentation to IPF [2]. Others have found no difference in survival and survival to IPF. In particular, RA patients were older Table 3 Clinical predictors of IPF CTD-ILD vs. CTD-UIP among those with IPF and general [12] diagnosis or with with more male predominance compared to other CTDUnivariable OR (95% CI) and did Pworse valuedespite similar Multivariable OR (95% CI) P value ILD, presenting PFT and autoimmune dominant lung fibrosis [26] not fitting CTD CT patterns among patients. A recent study Little is known about the pathologic Agecriteria. at biopsy 1.06mechanisms (1.03-1.09) <0.0001all CTD 1.06 (1.02-1.08) 0.0012 that lead to a common final pathway of UIP pattern yet dif- suggested better survival in comparison to case-matched Gender (male risk) 2.52 (1.44-4.49) 1.87 (0.95-3.7) 0.07 who received treatment [30]. While an ferent rates of disease progression and survival. An under- IPF controls <0.0001 Atypical findings on biopsy 0.99 (0.70-1.39) % pred = percent predicted. Complete case analysis (list-wise deletion). Multivariable adjusting for age, gender, smoking hx, FVC, and DLCO. Moya et al, Respir Res 2014 Duration of symptoms prior topresumptive biopsy 1.01 (0.99-1.02) standing of the perhaps inflammatory-based mechanisms that lead to UIP in CTD-ILD compared to the Positive autoimmune serology 0.08 (0.04-0.15) relatively unknown mechanisms in IPF may be helpful in FEVdeciphering 1.01 (0.99-1.03) 1, % pred future IPF treatment approaches. Our study highlights several insights in1.00 comparing FVC, % pred (0.98-1.02)biopsy% confirmed UIP in IPF and CTD. As1.01 most patients DLCO, pred (0.99-1.03) TLC, % pred 0.99 (0.98-1.02) Initial HRCT pattern Probable UIP 1.00 (0.42-2.27) Probable NSIP or inconsistent with UIP 0.40 (0.17-0.86) Atypical findings on biopsy 0.36 (0.19-0.69) % pred = percent predicted. Complete case analysis. 0.27 and histology 1.01are (0.99-1.03) NSIP CT pattern most common in CTD-ILD, recent work suggests CT features may <0.0001 0.09UIP (0.04-0.17) occur more frequently than previously noted [31] and is 0.17with underlying 1.03 (0.97-1.10) highly consistent UIP pathology [20]. Such radiologic0.61 features of advanced disease appear pre0.99 (0.92-1.07) dictive of survival in our cohort, 0.31 similar to IPF, 1.02though (0.99-1.05) similar presenting radiologic patterns were seen between 0.74and other CTD-UIP 0.98 (0.94-1.03) RA-UIP patients (predominantly atypical or probable UIP CT findings). As UIP pathology appears to bode worse survival, confirmatory biopsy in 0.98 0.79 (0.29-2.05) this subset of CTD-ILD particularly with atypical CT 0.02 0.31 (0.11-0.76) may not be unreasonable. Underlying mechanisms as to why RA-UIP may do poorly is0.56 currently unknown and 0.003 (0.27-1.22) the subject of ongoing study. Survival in IPF is known to be variable and may be affected by multiple factors including disease severity at the time of presentation and access to tertiary or expert care with earlier assessment [32]. Whether earlier diagnosis affects outcome remains tentative, as most patients with consistent UIP pattern on CT likely represent more advanced disease with worse survival. We note survival 0.19 <0.0001 0.27 0.73 0.15 0.36 0.64 0.01 0.56 3 18/04/15 Downloaded from http://thorax.bmj.com/ on February 21, 2015 - Published by group.bmj.com Interstitial lung disease Kliinis-‐radiologiset ennustetekijät Figure 4 Kaplan-Meier survival curve for connective tissue disease related fibrotic lung disease (CTD-FLD) -‐ Suurinta osa CTD-‐ILD:stä ei biopsoida patients based upon radiological presentation (n–168). -‐ AnalysoiDin kliinis-‐radiologisia ennustetekijöitä -‐ 168 CTD-‐ILD (51 biopsoitua) -‐ HRCT-‐luoki:elu: UIP, NSIP, määri:ämätön -‐ HRCT:n Downloaded trakDonbronkiektasiat ja hunajakennot sekä DLCO from http://thorax.bmj.com/ on February 21, 2015 - Published by group.bmj.com assosioituvat korkeaan kuolleisuuteen Interstitial lung disease Table 3 Observers’ HRCT scores for patients with CTD-FLD assigned a radiological diagnosis of fibrotic NSIP, UIP or indeterminate (n=168) Radiological diagnosis=fibrotic NSIP (n=144) Radiological diagnosis=UIP (n=15) Radiological diagnosis=indeterminate (n=9) p Value Total interstitial disease extent Ground-glass Reticulation Honeycombing Traction bronchiectasis Consolidation Honeycombing absent/present Traction bronchiectasis absent/present 27.3±19.7 10.0±13.2 16.7±12.7 0.2±0.2 3.7±3.2 1.4±4.8 141/3 42/102 37.7±18.1 3.7±6.9 25.7±14.6 7.5±2.8 9.4±8.7 1.6±1.3 0/15 0/15 31.0±18.4 9.4±14.9 18.6±11.4 0.1±0.28 4.9±3.1 1.1±1.6 6/3 1/8 CTD-FLD, connective tissue disease related fibrotic lung disease; NSIP, non-specific interstitial pneumonia; UIP, usual interstitial pneumonia. Walsh et al, Thorax 2013 bronchiectasis when compared with patients assigned a diagnosis of fibrotic NSIP or deemed to have an indeterminate HRCT pattern of disease (table 3). Honeycombing was identified in 21 cases (RA=10, SScl=3, MCTD=4, PM=0, SLE=3, Sjögren’s disease=1) and was the least frequent pattern identified overall. Traction bronchiectasis was identified in 125 cases (RA=33, SScl=22, MCTD=27, PM=26, SLE=8, Sjögren’s disease=9). All 15 cases assigned a radiological diagnosis of UIP had honeycombing and traction bronchiectasis on HRCT. On univariable analysis, ground glass opacification was the only parenchymal pattern, which was not associated with increased mortality (table 4). Radiological diagnosis was strongly associated with mortality (table 4, figure 4). On multivariable analysis, increasing severity of traction bronchiectasis, increasing extent of honeycombing and reduction in DLco independently associated with increased mortality (table 5). These results remained independently associated with increased mortality on subgroup analysis in patients with a radiological diagnosis of NSIP (and those with a radiological diagnosis of UIP (see online supplementary appendix, table 1)). On the basis of these results, the continuous traction bronchiectasis scores and honeycombing scores for each patient were converted to a simple binary absence/presence score. Interobserver agreement for the absence/presence of traction bronchiectasis was good (κw=0.69) and for the absence/presence of honeycombing was moderate (κw=0.50). A multivariable analysis, substituting the continuous traction bronchiectasis and honeycombing scores for these binary scores again demonstrated that the binary scores and DLco were the only variables independently associated with increased mortality (traction bronchiectasis absent/ present=HR 4.00, p=0.001, 95% CI 1.19 to 13.38, Akuu\ HR 95% CI Total interstitial disease extent Ground-glass opacification Fine reticulation Coarse reticulation Honeycombing Traction bronchiectasis Radiological diagnosis FVC %predicted FEV1%predicted DLco %predicted 1.02 0.99 1.04 1.06 1.13 1.10 4.37 0.99 0.98 0.96 1.01 0.97 1.01 1.01 1.07 1.05 2.20 0.98 0.42 0.94 to to to to to to to to to to p Value 1.04 1.02 1.06 1.11 1.19 1.15 8.62 1.01 1.02 0.99 Krooninen progressiivinen sis’ score, are associated with increasing mortality.4 <0.001 0.753 0.001 0.014 <0.001 <0.001 <0.001 0.394 0.511 <0.001 CTD-FLD, connective tissue disease related fibrotic lung disease. More of traction bronchiectasis also predicts increased mortality in Patients with biopsy proven UIP (n=25) had more severe fibrotic IIP.3 5 Although it is generally accepted that the predomdisease in terms of extent of disease as well as extent of reticulahistopathological patterns seen in CTD-FLD are UIP and tion, honeycombing and severity of traction inant bronchiectasis NSIP, for a number of reasons it is unclear if CT data when compared with those with biopsy proven fibrotic fibrotic NSIP derived from patients with idiopathic fibrotic lung disease can (n=26) (table 6). Patients for whom a histopathological diagnosis was available were divided into four categories be based upon a applied to CTD-FLD. First, CTD-FLD does not directly combination of the assigned radiological and established histoexactly replicate idiopathic fibrotic lung disease on histopathopathological diagnoses; (1) radiological and histopathological logical analysis. Fewer fibroblastic foci, prominent lymphoid gerdiagnosis of UIP (n=13—concordant UIP), (2) radiological diagminal centres, lymphoplasmacytic infiltrates and distinctive ILD ilmenee kun CTD jatkunut jo pitkään myofibroblast morphology are distinguishing features of Walsh et al, Thorax 2013 CTD-FLD.10 11 28 29 Second and most importantly, CTD-FLD appears to have a more favourable prognosis than fibrotic IIP.12 15 30 Despite these differences, our study has shown that traction bronchiectasis and honeycombing are also important predictors of mortality in CTD-FLD. The prognostic strength of traction bronchiectasis in our study is an important finding. Honeycombing is a cardinal fibrotic pattern on CT and most studies have focused the prognostic impact of this pattern4 26 rather than traction bronchiectasis. However, the interobserver agreement for the identification of honeycombing is surprisingly poor,31 32 best highlighted by Lynch et al who reported observer agreement levels for honeycombing among expert thoracic radiologists in a cohort of 315 patients with IPF as scarcely acceptable for clinical practice (weight κ coefficient of agreement no greater than 0.31).4 More recently, Watadani et al specifically quantified interobserver agreement for the presence of honeycombing among a large group of thoracic and non-thoracic radiologists as moderate (weighted κ coefficient of agreement=0.40–0.58).33 Disagreement was in most cases due to the presence of subpleural pathology mimicking honeycombing such as traction bronchiolectasis, paraseptal emphysema and subpleural cysts. These findings raise doubts as to whether honeycombing can always be relied upon as a prognostic CT pattern in routine clinical practice. The results of our study support those of others confined to IIPs3 5 9 and suggest that traction bronchiectasis may be a superior alternative CT sign for prognostication purposes in the CTD-FLDs Clinical applicability is an important consideration in a study of this kind. The continuous traction bronchiectasis and honeycombing scores are not easily applied to clinical practice and this led to the testing of a simplified binary absent/present score of these two patterns. Our study shows that simply the presence of traction bronchiectasis was a significantly more powerful prognostic index than the presence of honeycombing. Importantly, determining the absence or presence of traction bronchiectasis had a higher level of observer agreement than ILD CTD:n ensimmäisenä manifestaaDona 5 7 26 Subgroup analysis in patients with surgical lung biopsy data recently, two studies have demonstrated that increasing severity (n=51) • Kun tutkitaan IIP-‐poDlasta on syytä muistaa e:ä kyseessä voi olla myös CTD-‐ILD:n ensimmäinen manifestaaDo • ErityisesD tämä kanna:aa muistaa NSIP ja OP-‐ poDlaiden kohdalla, mu:a myös UIP/IPF-‐ epäilyissä nosis of fibrotic NSIP or indeterminate, with histopathological diagnosis of UIP (n=12—discordant UIP) (3) radiological diagnosis of UIP or indeterminate, with histopathological diagnosis of NSIP (n=9, discordant NSIP) and (4) radiological and histopathological diagnosis of fibrotic NSIP (n=17, Table concordant 5 Multivariable HRs for mortality according to HRCT and NSIP) This radiological-histopathological distinction wasindices in CTD-FLD (n=168) pulmonary strongly associated with increased mortality (HR 2.65, Variable UIP HR 95% CI p Value p<0.001, 95% CI 1.67 to 4.99). Patients with concordant had the highest mortality, while concordant NSIP was associated Honeycombing 1.08 1.04 to 1.17 0.022 with the lowest mortality. Discordant NSIP and discordant UIP Traction bronchiectasis 1.10 1.02 to 1.13 0.001 were associated with lower mortality than those with concord%predicted 0.96 0.94 to 0.98 0.001 ant UIP, but greater mortality than those with DLco concordant fibrotic NSIP (figure 5). Multivariable analysis demonstrated CTD-FLD, connective tissue disease related fibrotic lung disease. that severity of traction bronchiectasis (HR 1.07, p=0.001, 95% CI 1.01 to 1.13) and extent of honeycombing (HR 1.21, p=0.031, 95% CI 1.08 to 1.35) were the only220 independent variables independently associated with increased mortality in patients who underwent lung biopsy. Subkliininen Table 4 Crude HRs for mortality according to HRCT and pulmonary indices in CTD-FLD (n=168) Variable important HRCT predictors of mortality and traction bronchiectasis is the more powerful of the two. Second, the clinical utility thisCIfinding honeycombing absent/present=HR 2.87, p=0.022,of 95% 1.53 is enhanced by the superior level of interobserver to 5.43, DLco=HR 0.97, p=0.013. 95% CI 0.95 agreement to 0.99). Theassociated with an absent/present determination for traction when compared with the same determinprognostic strength of these binary scores was preserved on bronchiectasis subgroup analysis of the entire cohort with each CTD ationsubgroup for honeycombing. Lastly, our results suggest that in removed in turn, (see online supplementary appendix, tables 2patients with a histopathological diagnosis of UIP, but CTD-FLD, and 3). Two further analyses were performed: first, all analyses discordant radiological features, have a more favourable prognowere repeated after censoring of non-respiratory sis deaths (n=4). when compared with those with radiological and histopathoSecond, as vasculopathy with PAH may occur in patients with SScl logical UIP. (SScl-PAH) or SLE (SLE-PAH), which already confers a particuAlthough larly poor prognosis, a second analysis of all variables was per-there is a paucity of data on HRCT patterns, which prognosis in CTD-FLD, several studies have identified formed, censoring patients with SScl-PAH (n=10)predict or SLE-PAH prognostic (SLE-PAH=0). These analyses resulted in no appreciable changesHRCT patterns in the fibrotic (non-CTD related) 26 27 in significance of predictors or magnitude of their impact IIPs.4 5on7 surMany of these have demonstrated that increasing vival time estimates. reticulation, honeycombing or a combination of both as a ‘fibro- CTD-‐ILD:n monet muodot ILD on CTD:n ensimmäinen manifestaaDo 0.032 0.681 <0.012 <0.001 <0.001 0.843 Fulminan\, henkeä uhkaava Walsh SLF, et al. Thorax 2014;69:216–222. doi:10.1136/thoraxjnl-2013-203843 DISCUSSION Our study has demonstrated three novel findings in patients with CTD-FLD. First, honeycombing and traction bronchiectasis are Walsh SLF, et al. Thorax 2014;69:216–222. doi:10.1136/thoraxjnl-2013-203843 219 Respiratory Medicine (2009) 103, 1152e1158 available at www.sciencedirect.com journal homepage: www.elsevier.com/locate/rmed Mitä oireita ja löydöksiä pitäisi tarkistaa ILD-‐epäilyjen kohdalla? Ascertainment of collagen vascular disease in patients presenting with interstitial lung disease Shikha Mittoo a, Allan C. Gelber b, Lisa Christopher-Stine b, Maureen R. Horton c, Noah Lechtzin c, Sonye K. Danoff c,* Collagen vascular disease in ILD a Division of Rheumatology, University of Manitoba, Winnipeg Rheumatic Unit, RR149indicate Rehabilitation Hospital, and an Disease earlier study that CVD-UIP Table 5 Underlying rheumatologic diagnoses of CVD-ILD Health Sciences Centre, 800 Sherbrook Street, Winnipeg, MB, R3A 1M4, Canada 27,28 b survival5200 in comparison of Rheumatology, Johns Hopkins University School of Medicine, Eastern Avenue,with MasonIPF-UIP. F. Lord Center subjects by ACRDivision criteria. Tower, Suite 4100, Baltimore, MD 21224, USA 1157 has improved Our findings need be interpreted in light of the retro- -‐ 114 peräkkäistä ILD:tä tutki\in -‐ Oliko myös CTD? c Division ofdisease Pulmonary and Established Critical Care Medicine, University School of Medicine, 1830 E. Monument St, Diagnosis of rheumatic New Johns Hopkins spective study design. First, the decision to obtain 5th Floor, Baltimore, MD 21205, USA CVD-ILD, CVD-ILD, a particular serologic parameter and the manner in which n Z 17a n Z 17a the history and examination were conducted may have Received 3 October 2008; accepted 16 February 2009 been influenced by the individual patient’s symptoms and Systemic lupusAvailable online 21 March 2009 3 (18) 3 (18) the physician’s practice pattern. Future study in this area erythematosus, n (%) ought to incorporate a predetermined protocol for ascerIdiopathic inflammatory 5 (29) 10 (59) tainment of exposures and outcomes applied uniformly to Summary myositis, n (%)KEYWORDS Introduction: Previous studies of all interstitial lung disease (ILD) suggest thatwere prognosis therAntinuclear antibody; patients. Second, there 39andpatients among this Sjogren’s syndrome, n (%) 1 (6) 0 (0) apeutic response are influenced by the presence of underlying collagen vascular disease (CVD). Pulmonary fibrosis; cohort ofis ILD referrals forsought whom no autoantiSystemic sclerosis, n (%) lung disease; 1 (6)Yet, what proportion 1 (6) of patients consecutive presenting with ILD have CVD largely unknown. We Interstitial frequency of a bodies new CVD diagnosis an ILD referral population.of this quarter of the were intested. Exclusion vascular UndifferentiatedCollagen connective 0 (0)to determine the 2 (12) Materials/patients and methods:referent We retrospectively studied 114 consecutive patients evaludisease population due to missing data likely overtissue disease, n (%) ated at the Johns Hopkins Interstitial Lung Disease Clinic for the development of CVD. estimated the prevalence ofwith positive and Rheumatoid arthritis, n (%) 5 (29) (0) Results: In this0retrospective cohort, nearly one-third of the 114 patients confirmedautoantibodies ILD satisfied published Seventeen (15%) patients were diagnosed thediagnosis. frequency of new CVD diagnosis in with the remaining 114 Overlap syndrome, n (%) 2 (12) 0 (0)criteria for a CVD a new CVD as a direct consequence of their ILD evaluation. Patients with new CVDour diagnosis patients who formed the basis for analyses. However, Wegener’s granulomatosis, n (%) 0 (0)were younger 1than (6)those without new CVD diagnosis: 51.4 years (95% CI 45e58 years) and Tulokset -‐ Lähes kolmasosalla myös CTD -‐ 15 % :lla CTD tode\in ILD:n kanssa samaan aikaan -‐ ErityisesD myosii:eja tode\in ILD:n toteamisen kanssa samaan aikaan -‐ the Vasta-‐aineista korkea tuma-‐va, demographic profile of! the including 60 years (95%1CIpatient 57e63), respectively (p Z 0.01). Moreover, an ANA 1:640omitted (p Z 0.03) patients, and Percentages do not add to 100% due to rounding; elevated levels of creatine phosphokinase or aldolase (pa <ssosioituvat 0.001) were associated revealed no statistical differences age CK and ja (CPK) arace, ldolaasi Iwith LD:hen from the had lupus/myositis overlap and 1 patient had myositis, lupus, a new CVD diagnosis. a and scleroderma overlap. • Perifeerinen verenkierto – Raynaudin oire • Iho – Sklerodaktylia, sormihaavat ja –arvet, telangiektasia, iho:umat, mekaanikon kädet • Nivelet – Kipu, turvotus, aamujäykkyys • Lihakset – Kipu, heikkous • Suu ja silmät – Kuiva suu, kuivat silmät (sicca-‐oire) study population, suggesting that the treating physician’s Conclusions: Unrecognized collagen vascular disease may be more common than previously decision toHigh send overtly affected by appreciated among patients referred with ILD. titerautoantibodies ANA and an elevated was CPK ornot aldolase are associated with a CVD diagnosis in this referral population. demographic characteristics. On the other hand, as CVD is ª 2009 Elsevier Ltd. All rights reserved. Mi:oo et acenter. l, Respir often Med 2a 009 process in evolution, we would predict that to an ILD clinic at an academic tertiary care a number of individuals who did not meet criteria for CVD at Notably, 17 (15%) patients in this cohort were diagnosed the point of evaluation might subsequently do so. As one with a new CVD which satisfied published criteria, as such example, one of the non-CVD patients was seroposia direct consequence of their evaluation at the ILD clinic. In tive for Scl-70, an autoantibody with specificity for scleroaddition, we found that two-thirds (n Z 75) demonstrate at * Corresponding author. Tel.: þ1 410 955 4176; fax: þ1 410 955 0036. derma, but did not yet satisfy diagnostic criteria for that least one positiveE-mail autoantibody. The most common autoaddress: [email protected] (S.K. Danoff). disorder. Moreover, since the diagnostic criteria for a CVD antibodies were ANA and rheumatoid factor in 54% (n Z 61) 0954-6111/$ - see front matter ª 2009 Elsevier Ltd. All rights reserved. are used for research purposes, we may have missed CVD and 25% (n Z 28), respectively. A number of clinical and doi:10.1016/j.rmed.2009.02.009 cases diagnosed on clinical grounds. demographic parameters were further related to the The accurate recognition of CVD has significant therapeutic establishment of a new CVD diagnosis. This included and prognostic implication We, therefore, sought to deteryounger mean age at presentation, elevated levels of the mine what clinical characteristics and serologic assays used muscle enzymes, CPK and aldolase, and high titers of routinely in clinical practice might identify patients with an antinuclear antibody. underlying and heretofore unrecognized CVD. We found that The overall frequency of CVD in our population, while patients with a new CVD diagnosis were younger at including both established and new cases, was 30%: twice presentation, there were no other demographic features that that reported in the New Mexico ILD registry, where 13% of significantly associated with the presence of CVD. patients with ILD had CVD.26 This higher prevalence may One of the striking findings related to CVD status was the reflect the referral pattern at our tertiary care ILD clinic. frequency of high titer positive ANA: a high titer ANA was The relatively higher representation of lupus and myositis associated with a new CVD diagnosis. A homogeneous among the new CVD diagnoses in our cohort may similarly immunofluorescence ANA pattern was seemingly associated reflect the composition of our referent population or with established and new CVD diagnoses. In a separate practice patterns. Nevertheless, our findings emphasize study of 276 patients with systemic sclerosis, a homogethat a full range of CVD diagnoses may be observed in neous ANA pattern was associated with pulmonary patients referred to an ILD clinic. Our experience suggests fibrosis.29 In the same report, a centromere ANA pattern that myositis may be under-recognized in the ILD popwas negatively related to pulmonary fibrosis.29 Consistent ulation, as the levels of CK and aldolase are often not with these observations, in our study we found no patients markedly elevated and amyopathic forms of myositis with with a centromere pattern among the 61 patients with isolated lung disease does exist. We also find that at least a positive ANA and ILD. In contrast to a different recent one quarter of those with myositis and ILD who demonstudy,30 we did not find that rheumatoid factor predicted strate anti-synthetase antibodies do not express the Jo-1 4 18/04/15 Tavallisten CTD:n ensioireet, seulontakokeet ja merkkivasta-‐aineet /11"Ê £°Ê/>Û>ëiÊÃÞÃÌiiÃÌiÊÃ`iÕ`ÃÌ>ÕÌiÊiÃÀiiÌ]ÊÃiÕÌ>iiÌÊ>ÊiÀÛ>ÃÌ>>iiÌ°Ê6>ÀÃ>ÃiÌÊÀiÕ>>Ì ÌÃiÌÊÛiÌÕi `ÕÃiÌÊÊBÌiÌÌÞÊ«ÃÊÌ>ÕÕÃÌ>°Ê Ê Vasta-‐aine Tavallinen CTD assosiaa.o ANA > 1:320 Moni RF > 60 IU/ml RA, SjS, SLE AnD-‐CCP RA AnD-‐centromeeri SSc iÀÛ>ÃÌ>>iÊÊ Ì}iiÊ AnD-‐nuclear-‐ANA SSc ÛiÃBÀÞÌÊ>ÊÌÕÀÛÌÕÃiÌ]ÊÕÕiÕ]ÊÊ /Õ>Û>ÃÌ>>iiÌÊ Ê «iÀ à ÌÌÕ>]Ê iÀÞÞÃÊÊ Ê Ê >ÕÀ}i]Ê«iÕÀÌÌ >ÌÛ ÊÊ -Ê >ÃÃiÀÌiiÊ Ê 1, *«>ÀÌiÌÊ SS-‐A (anD-‐Ro) Moni *À>>ÀÊ-}ÀiÊÊ Ê ÃÞ`À>ÊÊ -ÕÕÊ>ÊÃiÊÕÛÕÕÃ]ÊÛiÃBÀÞÌ]ÊÊ Ê ÛBÃÞÞÃÊ ,iÕ>ÌiB]ÊÌÕ>Ê Ê Û>ÃÌ>>iiÌÊ --Ê,®Ê --Ê>®Ê ,, *«>ÀÌi Ê , «ÀÌiÊ SS-‐B (anD-‐La) SLE, SjS Sm (anD-‐Smith) SLE -i>ÕÌiÊÊ Ê Ã`iÕ`ÃÌ>ÕÌÊÊ Ê /®Ê >>À>>ÃiÌÊÃÀiÌ]Ê,>Þ>Õ`½ÊÊ Ê ÀiÞ ÌÞB]ÊÛiÃBÀÞÌÊ>ÊÌÕÀÛÊÊ Ê ÌÕÃiÌ]Ê-\Ê>Ì>ÃiÌÊ ÌÌÕ>ÌÊ ,iÕ>ÌiB]ÊÌÕ>Ê Ê Û>ÃÌ>>iiÌ 1£, *ÊÊ 1£, *«>ÀÌi AnD-‐ribonukleoproteiini (U1-‐RNP) SLE, MCTD *ÞÊ>Ê`iÀ>ÌÊ Ê ÞÃÌÌÊ Ê >ÃÌiÊ iÕÃÊ>Ê>ÀÕÕÃ]ÊÃBÊ Ê ÕiÊ>ÊÃÀiÊiÌ>>Ê Ê «ÕiÊ ÌÌÕ>Ê Ài>Ì>>ÃÊ Ê Ê £ÊÊ Ê Ê ÃÌ`ÞÞÃÀÌBBÊ Ê , ÃÞÌiÌ>>ÃÊ Ê Ê AnD-‐dsDNA (DNA) SLE Scl-‐70 (anD-‐topoisomeraasi) SSc -ÞÃÌiiiÊÊ Ê ÃiÀÃÊ Ê ,>Þ>Õ`½ÊÀiÞ ÌÞB]ÊÛiÃBÀÞÌ]ÊÊ Ê ÊÌÕÀ«>iÊ>ÊÌiÞÌÞÊ Ê i ,iÕ>ÌiB]ÊÌÕ>Ê Ê Û>ÃÌ>>iiÌÊ -VÇäÊÊ /«ÃiÀ>>ÃÊÊÊ AnD-‐tRNA syntetaasi va PM/DM (anDsyntetaasi-‐syndrooma) ÊÊ ÊÊ Ê Êdisease iÕÌÀwÊiÊÃÞÌÊ Ê «>Ã>>Ì}iiÌ Ê Ê Ê Ê Ê AnD-‐PM-‐Scl SSc/myosii\ overlapp AnD-‐Th/To SSc AnD-‐U3 ribonukleoproteiini SSc AnD-‐MDA-‐5 (CADM) Amyopaa\nen DM ->À>ÕÃÊ />Û>Ã>ÌÊiÃÀiiÌÊ -ÞÃÌiiiÊÕ«ÕÃÊ Ê iÀÞÌ i>ÌÃÕÃÊÊ Ê -®Ê -iÕÌ>iiÌÊ 6>ÃÕÌÌÊ ÕÕi]ÊÛiÊ>Ê >ÃÃBÀÞÌ]Ê ÊÊ >Ã]Ê Ài>ÌÛiÊÊÊÊ Ê Ê ÀiiÌ]ÊÕÕ>ÃÊ>ÊiÕ Ê Ê «ÀÌi]Ê«iÀÕÃÊ Downloaded from http://thorax.bmj.com/ on February 21, 2015 - Published by group.bmj.com Ê Ê ÕÕÌÃiÌÊ Ê ÛiÀiÕÛ>]ÊÛÀÌÃ>Ê Ê Ê Ê «iÀÕÃÌÕÌÕÃiÌÊ Interstitial lung --Ê,®Ê>Ê--Ê>®ÊrÊ-}ÀiÊÃÞ`À>ÊÊ>ÊÛ>ÃÌ>>iiÌ]Ê ÊrÊiÕÌÀwÊiÊÃÞÌ«>Ã>Û>ÃÌ>>iiÌÊ Julkunen H & Ekblom-‐Kullberg S, Duodecim 2004 Ê Ê reported on prognostic CT patterns, which are applicable to this 1ÃiÃÃ>Ê>LÀ>ÌÀÃÃ>Ê-]Ê, *]Ê--]Ê--]Ê£Ê>Ê-VÇäÛ>ÃÌ>>iiÌÊÃÃBÌÞÛBÌÊ Û>ÃÌ>>i`iÊBBÀÌÞÃiiÊiÝÌÀ>VÌ>LiÊ group as a whole, that is, idiopathic pulmonary fibrosis (IPF) and ÕVi>ÀÊ>Ì}iî°ÊÊ Ê Ê Ê Ê fibrotic NSIP.3 13 An advantage of this approach is Êthat prognosis can be predicted without the need to separate these two entities ,-/ÃÞ`À>Ê>ÃÃ]Ê,>Þ>Õ`½ÊÀiÞ ÌÞB]ÊÀÕ>ÌÀÛiÊ Þ«ÌÌiiÌÌ]ÊÃiÀ`>ÌÞ>]ÊÌii>}iÌ>Ã>Ì®ÊÊ >ÀÛ> on CT, which can often be problematic.14 iÊÃÞÃÌiiÃiÊÃiÀÃÊÛ>À>ÌÌ]Ê>ÊÃiÀ}iÊiÀÊÊÃiÌÀiiÀÛ>ÃÌ>>iÊÊ Ê Ê Ê Until now, there are no studies which have evaluated the Ê Ê Ê Ê Ê prognostic impact of CT patterns in a large group of patients with CTD-FLD. As individual CTD subsets often overlap clinic15 16 ally and on CT and most frequently present as either UIP or fibrotic NSIP on CT, the identification of prognostic patterns applicable across a variety of CTDs would be clinically useful. The purpose of this study was to investigate high resolution iÀÊmay Ã`iÕ`ÃÌ>ÕÌÊ Ã«Û>Ê ÌÞÞ« Û>Ê>>>°Ê-ÞÃÌiiÃÌiÊÃ`iÕ`ÃÌ>ÕÌiÊ computed tomography ÕÃi>«>>Ê (HRCT) patterns that predict prognosis in a variety of connective tissue diseases characterised by ÃBÊÃBÊÞ`ÃB]ÊÕÃiÊÞ `iÃÃBÊëiÃwÊÃiÊ Ì>ÊÊBÃÌiÌÞÊÌÕÀiiÃÃ>ÊÃÕ>>ÃiÃÃ>Ê« pulmonary fibrosis. Û>ÃÌ>>iiÊ>ÃÃ>]ÊiÃiÀÃÊÃi>ÕÌiÊ Ã`iÕ`ÃÌ>ÕÌÊ /®Ê >Ê 1£, *Û>ÃÌ>> Downloaded from http://thorax.bmj.com/ on February 21, 2015 - Published by group.bmj.com METHODS SSc «À>ÃÃ>Ê À«iLiÀ}> LiÀ}Ê >Ê ÌÌiÊ Downloaded from http://thorax.bmj.com/ on February 21, 2015 - Published by group.bmj.com ÓääÓ®° RA Figure 1 Axial high resolution computed tomography image at the level of thelung carina disease in a patient with systemicInterstitial sclerosis relatedlung fibrotic disease iÌ>°Ê->>>Ê«Ì>>>ÊÛÊ>ÊÞÃÊ>ÃÊiÀÊ Pulmonary function tests and HRCTs were clinically indicatedInterstitial lung disease. There is subpleural fine reticulation. Consensed scores at in all cases, and for theÃ`iÕ`ÃÌ>ÕÌ>Ê> `iÊÌ>Õ`ÊÀÌiiÀÌÊÌBÞÌÌÞ purposes of retrospective examination this level were: total disease extent=20%, reticulation=100%. Traction of which this data, informed to patient reported on prognostic CT patterns, are applicable this consent was not required by the bronchiectasis was grade=0. Table 1 Demographic data for the connective tissue disease ÛBÌ®]Ê Ì>Êwho Ã`iÕ`ÃÌ>ÕÌÊ iÃÌÞÞÊ Þ `iÃÃBÊ Ê ÃÀiÃÌ>Ê`>}à institutional Patients did not have a HRCT group as a whole, that is, idiopathic pulmonary review fibrosis board. (IPF) and related fibrotic lung disease (CTD-FLD) cohort (n=168), HRCT and lung function performed within three months of each fibrotic NSIP.3 13 An advantage of and this approach is thattests prognosis ÕÕÊ ÀiÕ>>ÌÌÃiÊ Ì>Ê `iiëiÃw selected pulmonary indices at time of CT were expressedÊÃiÊ as a >Õ percentage of the predicted values for the can be predicted without the needother to separate these twoThe entities were excluded. diagnosis of CTD-FLD was made fol14 Value patient’s age, sex and height.24 -ÞÃÌiiÃÌiÊ Ã`iÕ`ÃÌ>ÕÌiÊ iÃÀiiÌÊ >> Variable (n=168) on CT, which can often be problematic. ÌÕÕÌ>Õ`Ê>ÃÃ>ÊÀ>`ÊÞ°Ê£Ó]Ê lowing a clinical, radiological and when biopsy material was Until now, there are no studies which pathological have evaluated the of the patient data using the releavailable, review Age at the time of the scan; years±SD 53.9±10.9 ÀÊްʣȮ°Ê>ÃÃÃÌ>ÊÃ`iÕ`ÃÌ>ÕÌ>ÊÃ>À>à Û>ÌÊÕÃiÌiÊÛÕÃ>ÊiiÊÛ>ÀÃ>ÃiÊÌ>Õ`Ê 17–22 prognostic impact of CT patternsvant in asociety’s large group of patients The presence of pulmondiagnostic criteria. Gender; male/female 65/103 Statistical analysis with CTD-FLD. As individual CTD often clinicarysubsets fibrosis wasoverlap determined on HRCT by two radiologists of 9 Ì>ÛiÊÕÃÌ>ÊÞÌÞÞÊ>>ÀÞ B]Ê`iÊÃÃBBÊ ÌÌi>ÃÌ>°Ê-ÞÃÌiiÃiÃÃBÊÕ«ÕÃiÃÃ>Ê-®ÊÛÛiÊ Follow-up; months±SD, 64.3±31.8 15 16 Data are given as means with SDs, medians with IQR, or as ally and on CT and most frequently present as either UIP or respectively. years’ and 25 years’ experience, Current smoker; n(%) 6 (3.5) Ì>Õ`ÕÛ>ÊÊÃ>>>iÊÌ>Ê>ÊÌiÌÞÌÊ>ÕÌ iÃÀiÃÌ>Ê `>}ÃÊ Ê iÃBBÀÊ >ÃÊ number of patients and percentage where appropriate. Statistical fibrotic NSIP on CT, the identification of prognostic patterns A diagnosis of pulmonary arterial hypertension (PAH), if Ex-smoker; n(%) 60 (35.7) applicable across a variety of CTDs would be clinically useful. analyses were performed using STATA (V .12, StataCorp, College established by right heart catheterisation was also recorded. 102 (60.7) Û>ÃÌ>>iiÌÊÌÌÞÛBÌÊÌiÌÌÞ ÊÃÊÞ` ÛÕÌÌ>Ê iÀÛiÀ>Ê Þ°Ê £Î®]Ê >Ê «À>>ÀÃÃ>Ê - Never smoker; n(%) The purpose of this study was to investigate high Station, Texas). The single determination SD was used to evaluate Survival period wasresolution calculated starting from the date of the PA on RHC*; n(%) 20 (11.9) computed tomography (HRCT) patterns may to predict progÃÊiðÊÞÃÌÌiÊ>>ÀÞ BÌÊÌ>ÊvÃv«` }ÀiÊÃÞ`À>ÃÃ>ÊÃiÊ>ÊÃÕÕÊÕÛÕÕÃÊÊ interobserver agreement for continuous variables (total interstitial Total interstitial disease extent; mean±SD, 28.5±19.6 baselinethat HRCT the date of death, or in the case of survivors, nosis in a variety of connective tissue characterised disease extent, ground-glass opacification, fine and coarse reticulaglass opacification; mean±SD 9.4±12.7 to thediseases last known pointÛ>ÃÌ>>iiÌÊ>ÊÌÀLî° of by contact. In cases where patients were Û>Û>ÕÌÊ«Ì>ÃÌ>ÊiÃBBÀÊÇqÊÛÕÌÌ>]Êi Ground pulmonary fibrosis. tion, honeycombing, consolidation and emphysema).25 The Reticulation; mean±SD 15.6±14.6 lost to follow-up, status at the end of the study period was conHoneycombing; mean±SD 2.1±2.2 weighted κ statistic (κw) was used to evaluate interobserver agree/BÃÃBÊ>ÀÌiÃÃ>Ê« `Ì>>Ê>ÕëÌ>`iÊ iÊÕÊÀiiÊÞ`iÌBBÊi>ÊÃiÌÞÃÊ>Ì firmed by contacting the respective family practitioners. Consolidation; mean±SD 1.3±4.8 ment for categorical variables (traction bronchiectasis) and was METHODS ÃÞÃÌiiÃÌiÊ Ã`iÕ`ÃÌ>ÕÌiÊ `>}ÃÌ>>Ê À«iÊ ÓääÓ®°Ê ÃÊ≤0.40), ,>Þ>Õ`½Ê ÀiÞ ÌÞBÊ ÌÌÞÞÊ Traction bronchiectasis; mean±SD Figure 1 Axial high resolution computed tomography at the 4.5±4.5 Figurefair 3 (0.20<κ Axial thin wsection computed tomographic image in a patient categorised asimage follows: poor (0<κw≤0.20), Study population and clinical evaluation HRCT protocol and image evaluation level of the carinaÌÌÞÛBÊ in a patient with systemic sclerosis(0.40<κ related fibrotic Radiological diagnosis; UIP/fibrotic NSIP/indeterminate) 15/144/9 with rheumatoid arthritis related fibrotic lung disease. There is diffuse moderate (0.60<κ and excellent Pulmonary function tests and HRCTs were clinically indicated >ÊtheÕÌÌiÕÕÊ ÞÃÞÞÃB]Ê ÃÊ ià good >>Û>>Ê Ã`iÕ`ÃÌ>ÕÌ]Ê Û`>>Ê «iÀÕÃÌ>ÕÌÊ w≤0.60), w≤0.80) A detailed description of HRCT protocol, scoring method lung disease. There is subpleural fine reticulation. Consensed scores at ground glass opacification containing areas of marked traction 58.8±12.3 FEV1; % predicted in all cases, and for the purposes of retrospective examination thiscan levelbewere: total extent=20%, reticulation=100%. Traction and definitions of HRCT patterns found indisease the online bronchiectasis. Subpleural honeycombing is> `iÊ also present. ÛÕ`iÊ Consensed > FVC; % predicted iÀÌ>«>ÕÃÌiÊ Û>ÃÃ>°Ê 6>ÀÃ>ÃiÌÊ ÀiÕ>>Ì Ì`iÌ>Ê ÞiiÃBÊ iÃBÃiÊ 72.6±22.7 of this data, informed patient consent was not required by the scores at this level were: total disease extent=90%, ground glass repository. Briefly, two thoracic bronchiectasis radiologists was of grade=0. 9 years’ and DLco; % predicted 44.9±17.27 institutional review board. Patients who did not have a HRCT ÌÃiÌÊHRCTs ÛiÌÕi `ÕÃiÌÊ >>°ÊÃÕÃÊÃ`iÕ`ÃÌ>ÕÌiÊiÃÀiiÌÊ>>Û>ÌÊ opacification=80% and honeycombing=20%. Traction bronchiectasis 10 years’ experience scored for each patient on>Ê theÛ>ÃÕÌÌÊ ÌiÌ>>Ê *PA on RHC=pulmonary arterial hypertension diagnosed at right heart and lung function tests performed within three months of each was grade=3 within the ground-glass opacification in the right middle catheterisation. Total interstitial disease extent=sum of each of the individual HRCT extent of four was interstitial patterns (ground glassasopacification, were expressed a percentage of the predicted values for the other were excluded. The diagnosis of CTD-FLD made follobe and grade 2 in the honeycombing. patterns, except traction bronchiectasis, which was scored based upon severity within reticulation, honeycombing andand emphysema, patient’s age, sex height.24 lowing a clinical, radiological and when biopsy material wasand consolidation) each interstitial pattern and summated (see online supplementary appendix). -ÞÃÌiiÃÌiÊÃ`iÕ`ÃÌ>ÕÌiÊÕÌÃÕÕà at six levels. traction score was also assigned. £nÇÇ CTD-FLD, connective tissue disease related fibrotic lung disease; NSIP, non-specific available, pathological review of the patient dataA using the bronchiectasis rele(0.80<κw≤1.00).25 Cox regression analysis was used to identify interstitial pneumonia; UIP, usual interstitial pneumonia. Honeycombing defined as air-filled cystic spaces with The presencewas of pulmonvant society’s diagnostic criteria.17–22 associations between mortality and HRCT variables and pulmonirregular wallsradiologists deemed not representing traction bronchiectasis, Statistical analysis ary fibrosis was determined on HRCT by two of 9 ary function indices. One univariable model was built for total and traction bronchiectasis was defined irregular bronchial Data areasgiven as means with SDs, medians with IQR, or as years’ and 25 years’ experience, respectively. interstitial disease extent, traction bronchiectasis, each HRCT lung function was 6 days (IQR=1.0). There were 20 patients dilatation caused by(PAH), surrounding retractile number of pulmonary patients and fibrosis. percentage where appropriate. Statistical A diagnosis of pulmonary arterial hypertension if pattern score, FVC, FEV1 and DLco and a single multivariable with an established diagnosis of pulmonary arterial hypertension analysesdiagnosis were performed Lastly, observers provided a radiological for eachusing case STATA (V.12, StataCorp, College established by right heart catheterisation was also recorded. model was built using a backward elimination procedure for terms (RA-FLD=2, SScl=10, MCTD=5, PM=3, SLE=0, Sjögren’s Station, Texas). The This singleradiodetermination SD was used to evaluate selectingfrom fromthe UIPdate , fibrotic NSIP and indeterminate. Survival period was calculated starting of the found statistically significant (p<0.05) on univariable analysis. disease=0). A summary of patient demographics, radiological 23 agreement for continuous variables (total interstitial logical was based uponinterobserver current clinical guidelines. baseline HRCT to the date of death, or indiagnosis the case of survivors, The assumptions of linearity and proportional hazards were scores and pulmonary function tests are given in table 1. disease extent, ground-glass opacification, fine and coarse reticulaimages in figures 1–3. to the last known point of contact.Example In cases scores where with patients wereare given assessed by visual inspection of Martingale residuals and scaled Observer agreement for each of the HRCT patterns and traction 25 tion, honeycombing, consolidation and emphysema). The lost to follow-up, status at the end of the study period was conSchoenfeld residuals. bronchiectasis are shown in table 2. Interobserver agreement for weighted κ statistic (κw) was used to evaluate interobserver agreefirmed by contacting the respectivePulmonary family practitioners. radiological diagnosis assignment was good (κw=0.74). function tests ment for categorical variables (traction bronchiectasis) and was Assigned diagnoses were fibrotic NSIP (85.7%, 144/168), indeSpirometry ( Jaeger Master screen PFT, Carefusion, Warwick, UK), RESULTS image 1cm below categorised as follows: poor (0<κw≤0.20), fair (0.20<κ ≤0.40),computed tomography wsection Figure 2 Axial thin terminate (5.3%, 9/168) and UIP (8.9%, 15/168). Patients HRCT protocol and image evaluation plethysmographic lung volumes ( Jaeger Master screen Body, total of patients were identified. Of these, 47 patients moderate (0.40<κw≤0.60), good (0.60<κ w≤0.80) the dome of theand rightexcellent hemidiaphragm in aApatient with205 mixed assigned a radiological diagnosis of UIP had more extensive A detailed description of the HRCT protocol, scoring method Carefusion, Warwick, UK) and diffusion capacity for carbon monwereThere excluded because: connective tissue disease fibrotic lung disease. is patchy ground(1) on detailed evaluation of clinical reticulation and honeycombing and more severe traction and definitions of HRCT patternsoxide can be found( Jaeger in the Master online screen PFT, Carefusion, Warwick, (DLco) data, a multidisciplinary glass opacification and subpleural honeycombing, both containing diagnosis of CTD had not been secured repository. Briefly, two thoracic UK) radiologists of to 9 measure years’ and were used lung function according to established and (2) HRCT areas of traction bronchiectasis. Consensed(n=25) scores were at this level:not performed within 3 months of lung 10 years’ experience scored HRCTs for each onindices the were recorded: FEV1, FVC, total protocols. The patient following function test (n=22). The remaining 168 patients made up the total disease extent=85%, ground glass opacification=60%, extent of four interstitial patternslung (ground glass Table 2 Interobserver agreement for HRCT parenchymal patterns capacity andopacification, single breath carbon dioxide diffusing capacity study honeycombing=40%. Traction bronchiectasis waspopulation. grade=2 in This both group consisted of patients with a diagreticulation, honeycombing and consolidation) emphysema,concentration (DLco). These values expressed as the single determination SD for continuous variables nosis of rheumatoid arthritis (RA, n=39), scleroderma (SScl, corrected forand haemoglobin parenchymal patterns. at six levels. A traction bronchiectasis score was also assigned. and the weighted κ coefficient for categorical variables* (n=168) n=32), mixed connective tissue disease (MCTD, n=33), polyHoneycombing was defined as Walsh air-filled cystic spaces with myositis (PM, n=33), 217 systemic lupus erythematosus (SLE, Interobserver SLF, et al. Thorax 2014;69:216–222. doi:10.1136/thoraxjnl-2013-203843 irregular walls deemed not representing traction bronchiectasis, Pattern variation n=17) and Sjögren’s disease (n=14). Excluded patients did not and traction bronchiectasis was defined as irregular bronchial differ significantly in terms of functional impairment from the Total disease extent 1.0% dilatation caused by surrounding retractile pulmonary fibrosis. final study population. Histopathological confirmation of the Ground-glass opacification 6.2% Lastly, observers provided a radiological diagnosis for each case specific subtype of fibrosis (UIP/fibrotic NSIP) was available in Fine reticulation 0.1% selecting from UIP, fibrotic NSIP and indeterminate. This radio51 cases. During the study period, 48/168 patients died. Causes Coarse reticulation 8.8% logical diagnosis was based upon current clinical guidelines.23 of death were documented as progression of their interstitial Honeycombing 1.2% Example scores with images are given in figures 1–3. lung disease (n=44) and sepsis (n=3) and lung cancer (n=1). Study population and clinical evaluation Fischer & Richeldi, Semin Respir Crit Care Med 2014 DiagnosDset stepit • Varmennetaan systeeminen sidekudossairaus • Arvioidaan sopiiko ILD kyseiseen CTD:hen – HRCT • Suljetaan pois infekDot, lääke-‐reakDot ja muut intersDDaaliset keuhkosairaudet MCTD – BAL • Päätetään otetaanko keuhkobiopsia – Jos HRCT epätyypillinen kyseiselle CTD:lle tai jää epäspesifiseksi – Kun epäillään malignoomaa tai infekDota Walsh et al, Thorax 2013 Pulmonary function tests Spirometry ( Jaeger Master screen PFT, Carefusion, Warwick, UK), plethysmographic lung volumes ( Jaeger Master screen Body, Carefusion, Warwick, UK) and diffusion capacity for carbon monoxide (DLco) ( Jaeger Master screen PFT, Carefusion, Warwick, UK) were used to measure lung function according to established protocols. The following indices were recorded: FEV1, FVC, total lung capacity and single breath carbon dioxide diffusing capacity corrected for haemoglobin concentration (DLco). These values Of the 120/168 remaining patients, 105 were confirmed as alive at the end of the study period by reviewing the clinical records. Fifteen patients were lost to follow-up but subsequently confirmed as alive at the end of the study period by contacting the respective patients’ family practitioners. Of the 168 patients enrolled in the study, 103 were female. The mean age at the time of presentation was 55.9 years (SD=10.9 years). Median follow-up time was 64 months (IQR=38.4). The median interval between HRCT and baseline Milloin ILD-‐poDlas on syytä lähe:ää reumatologille? Figure 2 Axial thin section computed tomography image 1cm below the dome of the right hemidiaphragm in a patient with mixed connective tissue disease fibrotic lung disease. There is patchy ground glass opacification and subpleural honeycombing, both containing areas of traction bronchiectasis. Consensed scores were at this level: total disease extent=85%, ground glass opacification=60%, honeycombing=40%. Traction bronchiectasis was grade=2 in both parenchymal patterns. • Nainen, erityisesD alle 50 v. • Oireet Walsh SLF, et al. Thorax 2014;69:216–222. doi:10.1136/thoraxjnl-2013-203843 218 Consolidation Emphysema Traction bronchiectasis* Traction bronchiectasis absent/present* Honeycombing absent/present* Radiological diagnosis* (UIP/Fibrotic NSIP/ Indeterminate) 3.5% 1.3% 0.61 0.69 0.50 0.74 Milloin ILD-‐poDlas on syytä lähe:ää reumatologille?...(jatkuu ed. sivu) *denotes the categorical variables. NSIP, non-specific interstitial pneumonia; UIP, usual interstitial pneumonia. Walsh SLF, et al. Thorax 2014;69:216–222. doi:10.1136/thoraxjnl-2013-203843 217 – Raynaud’n oire, ruokatorven hypomoDlitee\, ranteiden tai metakarpaali-‐falangeaalinivelten tulehduksellinen artrii\, sormien turvotus, oireinen keratokonjunDviDs sicca • Histologia – NSIP, LIP tai muu ILD + extensiivinen pleurii\, Divis perivaskulaarinen kollageeni, lymfafollikkelit ja itukeskukset, runsaasD plasmasoluja • Serologiset löydökset – ANA > 1:320, RF > 60 IU/ml – AnD-‐Nucleolar-‐ANA (mikä tahansa Di:eri) – AnD-‐CCP, anD-‐Scl-‐70, SS-‐A, SS-‐B, anD-‐dsDNA, Sm, anD-‐RNP, anD-‐tRNA syntetaasi Fischer & Richeldi, Semin Respir Crit Care Med 2014 Fischer & Richeldi, Semin Respir Crit Care Med 2014 5 18/04/15 IIM-‐ILD ja anDsyntetaasi-‐syndrooma AnDsyntetaasi-‐syndrooma • Idiopaa\set inflammatoriset myopaDat (IIM) • ARS-‐va + IIM + ILD = anDsyntetaasi-‐syndrooma – PM, DM, inkluusiokappalemyosii\, amyopaa\nen DM – IIM-‐ILD prevalenssi 20-‐78% – ILD edeltää DM/PM-‐diagnoosia 13-‐37,5%:lla • Myosii\-‐spesifiset vasta-‐aineet – Ro52, MDA-‐5, 155/40, SRP, Mi-‐2, PM/Scl, ARS – Lisäksi nonerosiivinen artrii\, kuume, mekaanikon kädet, Raynaudin ilmiö – Eri ARS-‐vasta-‐aineet assosioituvat erilaisiin subfenotyyppeihin • Mikä tahansa ARS-‐va assosioituu korkeaan (67-‐100%) ILD:n kehi:ymisen riskiin – Jo-‐1 tavallisin: 15-‐30 % IIM-‐poDlaista – PL-‐12-‐, KS-‐, OJ-‐posiDivisilla suurin ILD-‐riski • AnDsyntetaasi-‐syndrooma vasta-‐aineet (ARS) – Jo-‐1, EJ, PL-‐7, PL-‐12, KS, OJ, Zo, YRS CTD-‐ILD:n histologiset ilmentymät CTD-‐ILD:n histologia • Kirurgisia keuhkobiopsioita otetaan harvoin – Tulevaisuudessa enemmän kryobiopsioita? • Histologia monimuotoisempaa kuin IIP:ssa – Monien alueiden (eri-‐aikaiset) affiisiot ja monien muutoksien yhdistelmät tyypillisiä – Parenkyymi (intersDDum), alveoli, ilmaDet, pleura, verisuonet voivat affisoitua – ”Acute on chronic” RA SLE PM/DM SSc SjS DAD 6% Harvoin 3-‐27% Harvoin Harvoin OP 11-‐15% Harvoin 5-‐40% 1% < 22% C-‐NSIP 12-‐15% 9% 7-‐73% 19-‐68% 3-‐28% F-‐NSIP 29-‐33% 4% 11-‐54% 59-‐68% 28-‐58% UIP 13-‐56% Harvoin 5-‐33% 15-‐26% < 17% CB 6% ? ? ? 78% FB 6-‐65% ? ? ? 11% OB/CB + ? ? Harvoin Harvoin Pleurii\ > 10 % 18-‐40% ? 67% ? ValDmomuut. + + + + Kyllä Urisman & Jones, Semin Respir Crit Care Med 2014 DAD = diffuusi alveolivaurio • Voi olla CTD-‐ILD:n ensimmäinen ilmentymä tai kroonisen taudin yhteydessä • Voi ilmetä (harvoin) minkä tahansa CTD:n yhteydessä • KliinisesD usein ARDS • Perustaudin akuu\en pahenemisvaiheiden tai infekDoiden yhteydessä – Akuu\en pahemisvaiheiden histologis-‐ radiologinen ilmentymä, myös IIP:ssa Organisoituva pneumonia (OP) ja bronkioliiDt (CB, FB, OB) • COP-‐diagnoosi (=idiopaa\nen) on poissulkua – OP voi olla infekDoiden, CTD:n, lääkereakDoiden, sädehoidon yhteydessä – CTD-‐ILD:ssa OP voi olla muiden muutosten joukossa • BronkioliiDt – Follikulaarinen (FB), sellulaarinen (CB) ja obliteroiva eli konstrikDivinen (OB) bronkiolii\ – Tavallisimpia RA:ssa ja SjS:ssa – Voivat olla ILD:n kanssa samanaikaisesD 6 18/04/15 [ Original Research Diffuse Lung Disease ] Pulmonary Function and Survival in Idiopathic vs Secondary Usual Interstitial Pneumonia KeuhkofunkDoiden käy:äytyminen IPF vs CTD-‐UIP Matthew J. Strand, PhD; David Sprunger, MD; Gregory P. Cosgrove, MD, FCCP; Evans R. Fernandez-Perez, MD, MPH, FCCP; Stephen K. Frankel, MD, FCCP; Tristan J. Huie, MD, FCCP; Amy L. Olson, MD, MSPH; Joshua Solomon, MD, FCCP; Kevin K. Brown, MD, FCCP; and Jeffrey J. Swigris, DO The usual interstitial pneumonia (UIP) pattern of lung injury may occur in the setting of connective tissue disease (CTD), but it is most commonly found in the absence of a known cause, in the clinical context of idiopathic pulmonary fibrosis (IPF). Our objective was to observe and compare longitudinal changes in pulmonary function and survival between patients with biopsy-proven UIP found in the clinical context of either CTD or IPF. BACKGROUND: We used longitudinal data analytic models to compare groups (IPF [n 5 321] and CTD-UIP [n 5 56]) on % predicted FVC (FVC %) or % predicted diffusing capacity of the lung for carbon monoxide (Dlco %), and we used both unadjusted and multivariable techniques to compare survival between these groups. METHODS: RESULTS: There were no significant differences between groups in longitudinal changes in FVC % or Dlco % up to diagnosis, or from diagnosis to 10 years beyond (over which time, the mean decrease in FVC % per year [95% CI] was 4.1 [3.4, 4.9] for IPF and 3.5 [1.8, 5.1] for CTD-UIP, P 5 .49 for difference; and the mean decrease in Dlco % per year was 4.7 [4.0, 5.3] for IPF and 4.3 [3.0, 5.6] for CTD-UIP, P 5 .60 for difference). Despite the lack of differences in pulmonary function, subjects with IPF had worse survival in unadjusted (log-rank P 5 .003) and certain multivariable analyses. Figure 1 – A, B, Change in FVC% (A) or DLCO% (B) over time for sample stratified on clinical context of UIP. Points represent observed values, with fitted (predicted) functions for groups (blue 5 IPF, red 5 CTD-UIP) superimposed; predicted means are solid, 95% confidence bands are dashed. Predicted values were obtained using mixed-model fits, using knots (ie, allowing change points) at 20.5, 0, 0.5, 1, and 2 y from diagnosis. A spatial power covariance structure was included in the model to account for repeated measures within subjects; random effect terms for subjects were also included, as described in e-Appendix 1. There were no significant differences between groups for segments between comparable time points. The plots demonstrate sharper declines near time of diagnosis for both groups. CTD-UIP 5 connective tissue disease-related usual interstitial pneumonia; DLCO% 5 % predicted diffusing capacity of the lung for carbon monoxide; FVC% 5 % predicted FVC; IPF 5 idiopathic pulmonary fibrosis. Despite no significant differences in changes in pulmonary function over time, patients with CTD-UIP (at least those with certain classifiable CTDs) live longer than patients with IPF—an observation that we suspect is due to an increased rate of mortal acute exacerbations in patients with IPF. CHEST 2014; 146(3):775-785 CONCLUSIONS: Strand MJ et al, Chest 2014 Strand MJ et al, Chest 2014 Manuscript received October 11, 2013; revision accepted March 3, 2014; originally Online First April only 3, 2014. In a Coxpublished model that contained the group variable ABBREVIATIONS: AEx 5 acute exacerbation pulmonary fibrosis; CTD 5 (IPF vs each of the four individual CTD categories, with connective tissue disease; CTD-UIP 5 connective tissue disease-related IPF as thepneumonia; reference D category), a signifi cant of orthe strong usual interstitial lco 5 diffusing capacity lung for carbon monoxide; 5 hazard ratio; interstitial lungfor disease; trend towardHR a protective effILD ect 5 was observed three IPF 5 idiopathic pulmonary fibrosis; NJH 5 National Jewish Health; subgroups RA 5 0.437,arthritis; P 5 .046; for PFT 5CTD pulmonary function(HR test; for RA 5 rheumatoid SScHR 5 systemic SSc sclerosis; UCTD 5 undiff connective tissue disease; 5 0.175, P5 .014; erentiated HR for other 5 0.550, P5 .10). UIP 5 usual interstitial pneumonia There was no significant difference in time to death for AFFILIATIONS: From the Division of Biostatistics (Dr Strand) and IPF vs UCTD (e-Fig 4).Interstitial Lung Disease Program Autoimmune Lung Center and (Drs Sprunger, Cosgrove, Fernandez-Perez, Frankel, Huie, Olson, Solomon, Brown, and Swigris), National Jewish Health, Denver, CO. Discussion Drs Brown and Swigris are co-senior authors. We identified Dr a cohort ofsupported patientsinwho, over a 25-year FUNDING/SUPPORT: Swigris is part by a Career Development Awardwere from diagnosed the National at Institutes of Health [K23 HL092227]. period, our center with UIP and met CORRESPONDENCE TO: Jeffrey J. Swigris, DO, Autoimmune Lung current diagnostic criteria for IPF or rheumatologistCenter and Interstitial Lung Disease Program, National Jewish Health, nedSt, CTD. WeCO examined whether pulmonary func1400defi Jackson Denver, 80206; e-mail: [email protected] © 2014 COLLEGE OF CHEST Reproduction tionAMERICAN over time or survival diffPHYSICIANS. ered between groups. of this article is prohibited written permission from American Interestingly andwithout surprisingly, there were nothesignifi cant College of Chest Physicians. See online for more details. differences in change (decline) over time DOI:between-group 10.1378/chest.13-2388 Elinaika IPF vs CTD-‐UIP Figure 2 shows spaghetti plots of raw data for withinsubject changes in FVC % and Dlco %: It is apparent that some subjects who experienced sharp declines around the time of diagnosis had shorter time of follow up. To systematically assess for the impact of this within-group, differential dropout, we stratified the groups on quartiles of time from diagnosis to last observed pulmonary Lee et al. function test (PFT) and refit models (e-Fig 1); within each quartile of time (, 0.42 years, 0.42-1.23 years, 1.24-3.33 years, ! 3.34 years), the proportions of subjects with IPF vs CTD-UIP, and the predicted mean FVC % at time of diagnosis, between subjects with IPF vs those with CTD-UIP were similar (see e-Appendix 1 for additional details). e-Figure 2 displays graphs of longitudinal changes in FVC % or Dlco % for subjects in the upper quartile of (ie, longest) time from biopsy to last PFT observation. Vasta-‐aineiden prevalenssi IPF vs terve 775 journal.publications.chestnet.org tiles of follow-up, but using data only from subjects with early (, 100 weeks) or late (! 100 weeks) time from diagnosis to last PFT observation, and including analyses on the individual CTD subgroups (eg, RA, SSc, UCTD, other), are displayed in Table 2 and Figure 3. Within groups (or CTD subgroups), subjects with last PFT observations , 100 weeks from biopsy generally had greater declines in lung function than subjects with late last PFT observations; however, significant betweengroups differences were not observed. In a logistic regression analysis, while controlling for age, sex, FVC %, and Dlco %, there was no significant difference between any individual CTD subgroup and IPF in the likelihood of last PFT observation ! 100 Page weeks 9 after biopsy (see e-Table 1 for detailed results). (P 5 .23 for difference). After diagnosis, the mean decrease in FVC % per year was 4.1 [3.4, 4.9] for IPF and 3.5 [1.8, 5.1] for CTD-UIP (P 5 .49 for difference); the mean decrease in Dlco % per year was 4.7 [4.0, 5.3] for IPF and 4.3 [3.0, 5.6] for CTD-UIP (P 5 .60 for difference). See e-Appendix 1 for more details. Figure 3 – A-B, Estimated mean FVC% (A) and DLCO% (B) by diagnosis group (IPF 5 blue, CTD-UIP 5 red) and last time of follow-up (, 100 wk, solid; ! 100 wk, dashed) based on linear mixed-model fits. Plots demonstrate that those with earlier last follow-up tended to have steeper declines in lung function. See Figure 1 legend for expansion of abbreviations. Downloaded From: http://journal.publications.chestnet.org/ by a University of Eastern Finland User on 03/02/2015 Survival $watermark-text Among subjects whose last PFT observation was within 100 weeks of diagnosis, there was no significant difference between groups in the proportion of subjects who died (IPF, 74% of 184 vs CTD-UIP, 69% of 29, P 5 .63); however, among those whose last observed PFT was ! 100 weeks after diagnosis, there was a difference between groups (IPF, 68% of 132 vs CTD-UIP, 42% of 26, P 5 .01). In the unadjusted analysis, survival was significantly longer in CTD-UIP than IPF (log-rank P 5 .003) (Fig 4). Median survival was 7.1 years (95% CI, 4.6-11.3) for CTD-UIP and 4.4 years (95% CI, 4.1-5.2) Nearly one-half of the subjects in each group (IPF or CTD-UIP) had their last PFT obtained , 100 weeks (1.92 years) after diagnosis. Results for additional analyses similar to those previously described for quar- [ 778 Original Research -‐ CTD-‐UIP:n elinaika pitempi kuin IPF:ssä vaikka keuhkofunkDoden kulku samanlainen journal.publications.chestnet.org -‐ IPF:ssä enemmän akuu:eja pahenemisvaiheita? Downloaded From: http://journal.publications.chestnet.org/ by a University of Eastern Finland User on 03/02/2015 Strand MJ et al, Chest 2014 781 146#3 CHEST SEPTEMBER 2014 ] Downloaded From: http://journal.publications.chestnet.org/ by a University of Eastern Finland User on 03/02/2015 $watermark-text Figure 4 – Kaplan-Meier survival curves for sample stratified on clinical context of usual interstitial pneumonia (IPF or CTD-UIP). See Figure 1 legend for expansion of abbreviations. Figure 1. -‐ Autovasta-‐aineet eivät ole IPF:ssa merki:äväsD korkeampia kuin terveillä The frequency of circulating autoantibody positivity in healthy controls (white bars) compared idiopathic=pulmonary (IPF, black There were no significant kontrolleilla (tomusta IPF, vfibrosis alkoinen = tbars). erve) differences in frequency of autoantibodies between healthy controls and IPF. “Other” includes double stranded deoxyribonucleic acid (dsDNA), chromatin, ribosomal P, anti-Ro (SS-A), anti-La (SS-B), centromere B, Smith (Sm), ribonucleoprotein (RNP), SmRNP, Lee et al, Respir Med 2013 Scl-70, Jo-1, proteinase 3 (PR3), myeloperoxidase (MPO) and glomerular basement membrane (GBM). Abbreviations: ANA – anti-nuclear antibody, RF – rheumatoid factor, CCP – cyclic citrullinated peptide. $watermark-text Mitä uu:a lääkityksestä? Rituksimabi vaikean CTD-‐ILD:n hoidossa CONNECTIVE TISSUE LUNG DISEASE TABLE 1 • Pirfenidonista, nintedanibista tai NAC:sta ei ole julkaistuja tutkimuksia CTD-‐ILD:ssa – Pirfenidoni faasi II SSc:ssa tehty, ei vielä julkaistu • Rituksimabista lupaavia tuloksia 3 tutkimuksessa – PM/DM-‐ILD, SSc-‐ILD – Vaikea etenevä CTD-‐ILD huolima:a korkea-‐ annoksisesta steroidista ja muusta immunosupressiivisesta lääkityksestä – Tutkimuksia meneillään G.J. KEIR ET AL. Baseline characteristics of patients treated with rituximab, including immunosuppressive therapy in the previous 12 months Patient Age/sex HRCT pattern Year of ILD Serum auto-antibody/CTD Pre-rituximab diagnosis features immunosuppression 2009 ENA, anti-Ro positive DM 2003 Anti-Jo 1, myositis Respir Med. Author manuscript; available in PMC 2014 February 01. Polymyositis/dermatomyositis 1 45/M 2 60/M Organising pneumonia/DAD Fibrotic NSIP* i.v. methylprednisolone on muscle biopsy MMF, prednisolone, cyclosporine i.v. cyclophosphamide 3 60/F Fibrotic NSIP 2000 Anti-Jo 1, myositis MMF, prednisolone i.v. rheumatoid factor cyclophosphamide MMF, prednisolone i.v. 4 29/F Fibrotic NSIP 2009 Anti-Jo 1, myositis anti-Ro cyclophosphamide 5 51/M Fibrotic NSIP 2005 Anti-Jo 1, myositis MMF, prednisolone i.v. 49/M Fibrotic NSIP 2006 ANA +++ (speckled) i.v. cyclophosphamide cyclophosphamide Undifferentiated CTD 6 7 37/F Organising 2009 pneumonia/DAD Raynaud’s, GORD prednisolone, MMF Rheumatoid factor i.v. methylprednisolone anti-CCP, anti-Ro Systemic sclerosis 8 63/M Fibrotic NSIP 1999 ATA MMF, prednisolone HRCT: high-resolution computed tomography; ILD: interstitial lung disease; CTD: connective tissue disease; M: male; F: female; DAD: diffuse alveolar damage; ENA: -‐ 7 poDlaalla ILD parani, yhdellä stabiloitui (keuhkofunkDot ja oireet) extractable nuclear antigen; DM: dermatomyositis; NSIP: non-specific interstitial pneumonia; MMF: mycophenolate mofetil; ANA: anti-nuclear antibody; GORD: gastrooesophageal reflux disease; CCP: cyclic citrullinated peptide; ATA: anti-topoisomerase antibody. *: fibrotic NSIP confirmed on surgical lung biopsy. Sem M Rheumatology 2009, Daoussis D Clin Exp Rheumatol 2012, Daoussis D Rheumatology 2010, Keir M Eur Respir J 2012, ClinicalTrials.gov cell reconstitution begins 6–9 months later [10]. Keir Evidence G, Eur forRthe espir occurred J 2012 in association with undifferentiated CTD, and in one effectiveness of B cell depletion exists in a number of immunewith SSc. All patients had failed to respond to conventional mediated conditions, including rheumatoid arthritis [11–13], immunosuppressive therapy, with ongoing deterioration in anti-neutrophil cytoplasmic antibody-associated vasculitis [14, 15], pulmonary function tests (PFTs) and/or worsening respiratory pulmonary alveolar proteinosis [16] and immune thrombocyfailure. At the time of referral, two patients were mechanically topenic purpura [17]. A few case series have suggest rituventilated and transferred directly to the intensive care unit ximab may also be effective in ILD occurring in the context of (ICU) of our hospital. Table 1 lists demographic information immunological over-activity, with favourable responses reported and immunosuppressive therapy in the 9–12 months prior to in anti-synthetase-associated ILD [18] and SSc-ILD [19]. Howrituximab therapy. ever, patients in these series had interstitial lung involvement of predominantly mild-to-moderate severity. Statistical analysis Evidence for the effectiveness of rituximab as ‘‘rescue’’ therapy in patients with severe, life-threatening ILD is limited [20, 21]. We report the use of rituximab as rescue therapy in eight patients with underlying features of CTD, and exceedingly severe fibrotic lung disease, progressing in spite of vigorous conventional immunosuppression. METHODS Patient groups Review of our medical records and hospital pharmacy prescribing database identified all patients treated with rituximab between December 2007 and December 2010. All consecutive patients with severe, progressive CTD-ILD were included in our analysis, with a total of eight patients. No patients with CTDILD were excluded due to poor outcome or early death. A minimum of 9 months post treatment follow-up was available for all patients. ILD occurred in association with polymyositis or dermatomyositis (PM/DM) in five patients, of whom four had anti-synthetase Jo-1 antibody. In two patients, ILD 642 VOLUME 40 NUMBER 3 All patients had PFT follow up of at least 9 months following rituximab. In the six patients with PFT data prior to rituximab treatment, the significance of median DL,CO and forced vital capacity (FVC) percentage change before and after treatment was assessed by Wilcoxon signed rank test. To evaluate statistical significance of response to treatment in all patients, categorical variables of change (worse, stable, improved) were generated by combining significant changes in pulmonary function tests (defined as a change in FVC of o10% and/or a change in DL,CO of o15%) and/or clinical status (for the two patients requiring mechanical ventilation, the requirement for mechanical ventilation was classified as a significant deterioration). Change was assessed 9–12 months before and after rituximab, and analysed using the Wilcoxon signed-rank test. A p-values of o0.05 was considered statistically significant. Analysis of follow-up data at 9–12 months was chosen based upon previously reported responses of CTD-ILD to rituximab [18, 19], and the expected duration of B cell ablation following rituximab [10, 15]. EUROPEAN RESPIRATORY JOURNAL 7 that a subset of this patient population may eventually meet the criteria for a well-defined CTD. These findings demonstrate that identification of subtle CTD clinical features, when associated with presence of auto-antibodies, do impact on the clinical and imaging presentation of ILD and are associated with distinct attributes. In other words, subtle manifestations of CTD should be considered in a patient evaluated for ILD, even if overt CTD criteria are not fulfilled. In another study, CORTE et al. [6] elegantly demonstrated that the proportion of patients with idiopathic interstitial pneumonia that fulfil UCTD criteria is dependent on the criteria used (table 3). Using ‘‘broad criteria’’ [5], UCTD could be diagnosed in 36% of patients with IPF and in 71% of patients with NSIP, whereas UCTD was considered to be present in only 13% and 21%, respectively, of the same patients groups using the more stringent criteria of UCTD [40]. The presence of UCTD was associated with a higher frequency of NSIP histopathology [6]. 18/04/15 In a recent study, FISCHER et al. [17] suggested the terminology of lung-dominant CTD to account for the subset of patients with interstitial pneumonia who have clinical features suggesting an associated CTD, but the features fall short of a clear diagnosis of CTD under the current rheumatologic classification systems. The proposed provisional criteria for this condition include four criteria: 1) a histological or radiological pattern of NSIP, UIP, lymphocytic interstitial pneumonia, organising pneumonia or diffuse alveolar damage; 2) insufficient extra-thoracic features of a definite CTD to allow a specific CTD designation; 3) no identifiable alternative aetiology for interstitial pneumonia; 4) any one of a list of auto-antibodies or at least two of four predefined histopathology features (lymphoid aggregates with germinal centres, extensive pleuritis, prominent plasmacytic infiltration and dense perivascular collagen). Such provisional conceptual classification carries the advantage of setting the stage for future studies of the prognostic, therapeutic and pathobiological implications of CTD features in patients with ILD. However, the proposed criteria need further refinement based on evidence, especially since they imply that patients may be classified as having UCTD:n diagnosDset kriteerit Epäspesifinen sidekudostauD ja ILD TABLE 3 Diagnostic criteria for undifferentiated connective tissue disease (UCTD) UCTD diagnostic criteria Broader definition of UCTD • UndifferenDated connecDve Dssue disease A. Symptoms associated with CTD At least one of: 1) Raynaud’s phenomenon; At least one of: 1) Raynaud’s phenomenon; associated ILD = UCTD-‐ILD 2) arthralgias/multiple joint swelling; 3) morning 2) arthralgias/multiple joint swelling; 3) photosensitivity; stiffness; 4) dry mouth or dry eyes (Sicca 4) unintentional weight loss; 5) morning stiffness; • Autoimmune-‐featured intersDDal lung disease features); 5) proximal muscle weakness 6) dry mouth or dry eyes (Sicca features); 7) dysphagia; 8) recurrent unexplained fever; 9) gastro-oesophageal reflux; 10) skin changes (rash); • Parhaillaan tekeillään ATS/ERS suositus, jossa 11) oral ulceration; 12) nonandrogenic alopecia; 13) proximal muscle weakness nimeksi ehdotetaan B. Positive autoimmune serology Positive finding of at least one of: 1) ANA Positive finding of at least one of: 1) ANA; 2) RF; (high titre); 2) RF (high titre); 3) positive ENA; 3) anti-Scl70 antibody; 4) SS-A or SS-B; 5) Jo-1 • IntersDDal pneumoniDs with autoimmune-‐ 4) anti-Scl70 antibody; 5) anti-RNP antibody; antibody; 6) ESR (.2 times normal), CRP 6) anticentromere antibody; 7) SS-A or SS-B; features 8) Jo-1 antibody CTD: connective tissue disease; ANA: antinuclear antibody; RF: rheumatoid factor; ENA: extractable nuclear antigen; RNP: ribonucleoprotein; • Useita tutkimuksia v. 2007 alkaen SS-A: anti-Ro; SS-B: anti-La; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein. : a diagnosis of UCTD requires having one or more of # TABLE 2 ] Comparison of the Baseline Features Between the UCTD-UIP and UCTD-NSIP Groups Features TABLE 2 ] Comparison of the Baseline Features Between the UCTD-UIP and UCTD-NSIP Groups Features UIP Patient number 44 (41.9) Age, y 62.8 ! 8.0 Sex, male 15 (34.1) 6 (20.7) Smoking (ever smoker) 16 (36.4) 6 (20.7) BAL (UIP: No. 5 34; NSIP: No. 5 18) WBC count, /mL 297.7 ! 304.1 287.7 ! 191.0 12.1 ! 17.2 5.9 ! 7.1 Neutrophil, % Lymphocyte, % 17.5 ! 18.2 18.1 ! 16.9 71.4 ! 15.1 68.4 ! 16.2 Baseline PFT (UIP: No. 5 44; NSIP: No. 5 29) FVC, % FEV1, % [ 81.7 ! 16.4 DLCO, % TLC, % Research Diffuse Lung Disease Original 6MWT, distance 55.3 ! 16.0 55.0 ! 15.3 69.4 ! 14.2 437.5 ! 94.7 464.1 ! 90.3 DLCO, % .424 TLC, % .246 6MWT, distance .930 Patient number Treatment regimen Steroid only Steroid 1 immunosuppressant None Stable Deterioration Median follow-up, mo Survival (%) Treatment regimen P Value tissue disease (UCTD) involves conditions char-‐ connective 788 IIP-‐poDlasta 2005-‐2012 acterized by both having symptoms of connective tissue disease (CTD) and autoantibodies but -‐ AnalysoiDin uudestaan not fulfilling the criteria of a specifi c CTD. The frequency or prognosis of the usual interstitial pneumonia (UIP) pattern in UCTD is unknown, which may be confused with idiopathic pul-‐ UCTD-‐kriteerit tarkiste\in monary fibrosis (IPF). This study aimed to investigate the frequency of the UIP pattern in 105 UCTD-‐ILD-‐poDlasta that of IPF and interstitial pneumonia related-‐ to UCTD and compare its prognosis with UCTD-nonspecific interstitial pneumonia -‐ 4(UCTD-NSIP). 4 UIP, 29 NSIP, 9 OP Steroid only .695 17 (38.6) 13 (44.8) 14 (31.8) 10 (34.5) 13 (29.5) 6 (20.7) 17 (38.6) 13 (44.8) Steroid 1 immunosuppressant 14 (31.8) 10 (34.5) None 13 (29.5) 6 (20.7) 5 (16.1) 3 (13.0) 6 (20.7) .153 TABLE 5 19 (61.3) 17 (73.9) 7 (22.6) 3 (13.0) Improvement Stable Deterioration Th medical records of 788 patients presumptively diagnosed with idiopathic inter3 e(13.0) Median2012 follow-up, stitial pneumonia at Asan Medical Center from January 2005 to December weremo retro19 (61.3) 17 (73.9) Survival (%) spectively 7 (22.6) reviewed. 3 (13.0) UCTD was diagnosed according to the criteria by Corte and colleagues, 1y and 21 the prognoses were 44 … compared between UCTD-UIP and UCTD-NSIP and between 3y UCTD-UIP and IPF. .021 METHODS: 5 (16.1) ] Comparison Between IPF and UCTD-UIP Features # Patient number IPF 287.7 ! 191.0 5.9 ! 7.1 Sex, male .900 Co\n .173 V, Eur Respir Rev 2Smoking 013 (ever smoker) 17.5 ! 18.2 18.1 ! 16.9 .920 71.4 ! 15.1 68.4 ! 16.2 .424 81.7 ! 16.4 76.9 ! 18.4 .246 55.3 ! 16.0 55.0 ! 15.3 .930 71.5 ! 11.5 69.4 ! 14.2 .494 464.1 ! 90.3 Surgical lung biopsy Comparison of the Survival Between IPF and UCTD-UIP UCTD-‐NSIP vs UCTD-‐UIP P Value 21 44 97.7 96.6 76.6 96.6 , .005 16 (36.4) , .005 24 (54.5) .080 204 (40.9) WBC count, /mL 204.0 ! 343.1 297.7 ! 304.1 Neutrophil, % .122 9.6 ! 16.3 277 12.1 ! 17.2 .384 9.8 ! 12.4 17.5 ! 18.2 .001 FVC 71.9 ! 19.7 71.4 ! 15.1 .890 FEV1 82.7 ! 20.2 81.7 ! 16.4 .745 DLCO 59.2 ! 21.5 55.3 ! 16.0 .242 Lymphocyte, % TLC 71.5 ! 11.5 .811 410.4 ! 122.6 437.5 ! 94.7 .155 26 31 1y 82.3 97.7 3y 57.8 76.6 6MWT, distance 72.2 ! 17.3 Median follow-up, mo Survival (%) 3y 97.7 RESULTS: … .042 Values are reported as mean ! SD or as frequency (%). IPF 5 idiopathic pulmonary fibrosis. See Table 1 and 2 legends for expansion of other abbreviations. total subjects. Vij et al7 reported that the prevalence of autoimmune-featured ILD was 52% of presumable IIP; however, their criteria included several nonspecific features as mentioned previously. UCTD-‐UIP vs IPF … .695 … .021 Figure 1 – Comparison of the survival curves of the patients with UCTD-UIP and UCTD-NSIP. NSIP 5 nonspecific interstitial 15 (34.1) 355 (71.1) Baseline PFT, frequency (%) (IPF: No. 5 481; UCTD-UIP: No. 5 44) Ennuste The baseline characteristics of the IPF and UCTD-UIP groups were summarized in Table 5. Kaplan-Meier survival analysis showed significantly better prognosis of the UCTD-UIP group (n 5 44) than the IPF group (P 5 .042) (Fig 2). The univariate Cox proportional … .069 390 (78.2) Figure 2 – Kaplan-Meier survival curves of the patients with UCTD-UIP and IPF. IPF 5 idiopathic pulmonary fibrosis. See Figure 1 legend for Although the frequency of UCTD was three times higher in the NSIP than in the UIP pattern, our current study showed that in patients with ILD and UCTD, the UIP pattern was as frequent as or more frequent than the NSIP pattern, which was consistent with the findings of Vij et al7 (25 UIP pattern vs two NSIP pattern among 63 patients with autoimmune-featured ILD). We also confirmed that among the patients with UCTD, the overall prognosis was better for patients with the NSIP pattern than those with the UIP pattern, although not significant on multivariate analysis. Furthermore, Kaplan-Meier survival analysis showed a significant difference between UCTD-UIP and IPF; the presence of UCTD in the patients with the UIP pattern was a significant independent prognostic factor on multivariate analysis. Previously, Corte et al4 reported that UCTD was not associated with a survival benefit, which may be due to smaller numbers (total 101 patients) of the subject compared with ours. Recently, Strand et al21 also reported that there was no significant difference in survival between UCTD-UIP and IPF. However, the number of their subjects was small (UCTD-UIP: 19 patients). Furthermore, there was no mention about the diagnostic criteria of UCTD, which may affect the expansion of other abbreviations. reported as frequency (%). See Table 1 legend for expansion pneumonia; UCTD 5 undifferentiated connective tissue disease; 96.6 Among 105 patients with UCTD (13.3% of total subjects),Values 44 are had a UIP pattern UIP 5 usual interstitial pneumonia. of abbreviations. 96.6 1 – Comparison of CT the survival patients with (by surgical lung biopsy: 24; byFigure high-resolution scan:curves 20), of29thehad a nonspecifi c interstitial UCTD-UIP and UCTD-NSIP. NSIP 5 nonspecific interstitial 170 Original Research Values are reported as frequency (%). See Table 1 legend for expansion UCTD 5 undiff connective tissue disease;pneumonia pattern pneumonia pattern (by surgicalpneumonia; lung biopsy), and erentiated nine had an organizing 168 Original Research [ 1 4 7 # 1 C H E S T J A N UKim A RY 2H 0 1C 5 e ] t al, Chest 2015 UIP usual interstitial of abbreviations. HC eof5t the al, UCTD-UIP C hest pneumonia. 2015 (by biopsy). The overallKim survival group was shorter than that of the UCTDDownloaded From: http://journal.publications.chestnet.org/ by a University of Eastern Finland User NSIP group (P 5 .021) but significantly better than that of the IPF groupFrom: (P 5http://journal.publications.chestnet.org/ .042). Downloaded by a University of Eastern Finland User on 03/02/2015 168 Original Research [ 147#1 CHEST JANUARY 2015 ] CONCLUSIONS: A UIP pattern, which seems to be frequent in UCTD, showed a poorer prognosis than thatby ofaUCTD-NSIP. However, the prognosis Downloaded From: http://journal.publications.chestnet.org/ University of Eastern Finland User on 03/02/2015of UCTD-UIP was significantly better than that of IPF, highlighting the importance of searching for underlying UCTD in suspected IPF cases. CHEST 2015; 147(1):165-172 1y 44 62.8 ! 8.0 BAL (IPF: No. 5 426; UCTD-UIP: No. 5 34) .234 group (62.8 ! 8.0 years) (e-Table 1). And the survival of these patients was also similar to that of the UCTD-UIP group (e-Fig 1). P Value UCTD-UIP 499 .619 Treatment response (UCTD-UIP: No. 5 31; UCTD-NSIP: No. 5 23) .619 16 (36.4) 437.5 ! 94.7 the pathologic pattern was not confirmed in 23 patients, the clinical features and survival curves of these patients were compared separately. As shown in group (62.8 ! 8.0 years) (e-Table 1). And the survival of Table 2, there was no difference in the clinical features these patients was also similar to that of the UCTD-UIP between UCTD-UIP and UCTD-NSIP except age and group (e-Fig 1). the age of these 23 patients with uncertain pathologic Comparison of the Survival Between pattern was 62.0 ! 11.1 years, similar to UCTD-UIP 44 29Undifferentiated … BACKGROUND: Treatment response (UCTD-UIP: No. 5 31; UCTD-NSIP: No. 5 23) Improvement UCTD-NSIP .216 .494 Values are reported as mean ! SD or as frequency (%). 6MWT 5 6-min walk test; DLCO 5 diffusing capacity of the lung for carbon monoxide; PFT 5 pulmonary function test; TLC 5 total lung capacity. See Table 1 legend for expansion of other abbreviations. .234 Interstitial Pneumonia Related to Undifferentiated Connective Tissue Disease UCTD-UIP 6 (20.7) 12.1 ! 17.2 Because the pathologic pattern was not confirmed in 23 patients, the clinical features and survival curves of these patients were compared separately. As shown in Table 2, there was no difference in the clinical features between UCTD-UIP and UCTD-NSIP except age and IPF and UCTD-UIP the age of these 23 patients with uncertain pathologic The baseline characteristics of the IPF and UCTD-UIP pattern was 62.0 ! 11.1 years, similar to UCTD-UIP TABLE 3 ] Clinical Course of the Patients With groups were summarized in Table 5. Kaplan-Meier Ho-Cheol Kim, MD; Wonjun Ji, MD; Mi Young Kim, MD, PhD; Thomas V. Colby, MD, PhD; Se Jin Jang, UCTD-UIP MD, PhD;and UCTD-NSIP survival analysis showed significantly better prognosis Characteristics UCTD-UIP UCTD-NSIP Chang-Keun Lee, MD, PhD; Seung Bong Han, PhD; and Dong Soon Kim, MD, PhD of the UCTD-UIP group (n 5 44) than the IPF group TABLE 3 ] Clinical Course of the Patients With Patient number 44 29 UCTD-UIP and UCTD-NSIP (P 5 .042) (Fig 2). The univariate Cox proportional Characteristics … , .005 15 (34.1) 297.7 ! 304.1 Values are reported as mean ! SD or as frequency (%). 6MWT 5 6-min walk test; DLCO 5 diffusing capacity of the lung for carbon monoxide; Because PFT 5 pulmonary function test; TLC 5 total lung capacity. See Table 1 legend for expansion of other abbreviations. Pathologic Pattern and Prognosis 29 (27.6) 52.5 ! 9.3 Age, y 65.1 ! 7.9 one or more of the laboratory findings listed in B; ": criteria proposed by K INDER et al. [5]. Reproduced from [6] with Lymphocyte, % .900 Baseline .173 PFT (UIP: No. 5 44; NSIP: No. 5 29) FVC, % DOI: .920 10.1183/09059180.00003013 FEV1, % 76.9 ! 18.4 71.5 ! 11.5 ] 62.8 ! 8.0 Smoking (ever smoker) , .005 (UIP: No. 5 34; NSIP: No. 5 18) theBAL symptoms outlined in A, and .216 WBC count, /mL .153 permission. Neutrophil, % P Value NSIP 44 (41.9) PAge, Valuey Sex, … male 29 (27.6) 52.5 ! 9.3 UIP Patient number NSIP #," 76.6 Manuscript received February 2, 2014; revision accepted August 10, 2014; originally published Online First September 11, 2014. ABBREVIATIONS: ANA 5 antinuclear antibody; CTD 5 connective tissue disease; Dlco 5 diffusing capacity of the lung for carbon monoxide; ENA 5 extractable nuclear antigen; HRCT 5 high-resolution CT; IIP 5 idiopathic interstitial pneumonia; ILD 5 interstitial lung disease; IPF 5 idiopathic pulmonary fibrosis; NSIP 5 nonspecific interstitial pneumonia; OP 5 organizing pneumonia; RF 5 rheumatoid factor; UCTD 5 undifferentiated connective tissue disease; UCTD-IP 5 interstitial pneumonia related to undifferentiated connective tissue disease; UIP 5 usual interstitial pneumonia AFFILIATIONS: From the Department of Pulmonary and Critical Care Medicine (Drs H.-C. Kim, Ji, and D. S. Kim) and Department of Radiology (Dr M. Y. Kim), Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea; Department of Laboratory Medicine and Pathology (Dr Colby), Mayo Clinic, Scottsdale, AZ; and the Department of Pathology (Dr Jang), Division of Rheumatology, Department of Internal Medicine (Dr Lee), and Department of Clinical Epidemiology and Biostatistics (Dr Han), Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea. Drs H.-C. Kim and Ji contributed equally as the co-first authors. FUNDING/SUPPORT: The authors have reported to CHEST that no funding was received for this study. CORRESPONDENCE TO: Dong Soon Kim, MD, PhD, Department of Pulmonary and Critical Care Medicine, Asan Medical Center, College of Medicine, University of Ulsan, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, South Korea 138-736; e-mail: [email protected] © 2015 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.14-0272 Haku • 7.11.2011 haku OYS – Hoidonpää:ämisaineisto – Poliklinikkarekisteri journal.publications.chestnet.org • Ajanjakso 1.11.2010-‐7.11.2011 • Dg-‐nrot: J84.0, J84.1, J84.8, J84.9 • Ensisijainen tavoite: kolmoislääkitystä käy:ävien poDlaiden selvi:äminen Downloaded From: http://journal.publications.chestnet.org/ by a University of Eastern Finland User on 03/02/2015 – poDlaiden määrä /eri tauDtyypit 165 [ 147#1 CHEST JANUARY 2015 on 03/02/2015 PoDlaat • Haussa saaDin noin 200 poDlaasta • Mukaan ote\in 188 poDlasta, loput poissulje\in – Väärä dg-‐nro – Muun sairaalan kuin OYS:n poDlas (esim biopsiano:oa varten OYS:ssa) – 1 obliteroiva bronkiolii\ – Parantunut Dlanne (aluperin epäilty fibroosia mu:a ollutkin esim tulehdus) 8 ] 18/04/15 PoDlasryhmät • • • • • • • • IPF: 60 NSIP: 26 CTD-‐ILD: 33 UIP:n ja NSIP:n piirteitä, epäselvä fibroosi: 35 COP, OP: 16 Asbestoosi: 10 DIP, RBILD: 5 AIP, ARDS (H1N1), akuu\ keuhkovaurio: 3 RA-‐ILD (15) • • • • • • RA-‐UIP: 5 RA-‐NSIP: 5 Epäselvä ILD eli RA-‐ILD: 4 (joista yksi ehkä UIP) RA-‐OP-‐epäily (nivelreumatutkimukset kesken) 1 AEx, johon exitus 1 keuhkonsiirto tehty (RA-‐UIP) CTD-‐ILD (33) • • • • • • • RA-‐ILD: 15 SSc-‐ILD: 4 SLE-‐ILD: 3 SjS-‐ILD: 2 PM/DM-‐ILD: 5 Selkärankareuma: 2 Epäselvä sidekudostauD (UCTD?): 2 PM/DM-‐ILD, SjS, selkärankareuma ja epäselvä sidekudostauD • 4 PM-‐ILD, 1 DM-‐ILD – 3 NSIP – 2 luoki:elematonta • SjS-‐ILD – 2 luoki:elematonta • Selkärankareuma – 1, jossa hunajakennoa, biopsiassa aikanaan DIP – 1 OP • Epäselvä sidekudostauD – 2 NSIP Johtopäätökset Kiitos! • Eri:äin haastava tauDryhmä – Yksi:äiset tauDyhdistelmät harvinaisia – Ryhmänä kohtalainen yleinen esh:ssa – Toisinaan sekä ILD e:ä CTD epäselviä • MoniammaDllinen yhteistyö keuhkolääkärin, reumatologin, radiologin ja joskus myös patologin kanssa tärkeää • Tarvitaanko kansallista yhteistyötä keuhkokeskusten välillä? 9
© Copyright 2024